Persistent trophoblastic atypia on endocervical curettage found to be an epithelioid trophoblastic Tumor: A case report and review of the literature.

We present an unusual case of a 28-year-old female who had atypical trophoblastic proliferation on her endocervical curettage (ECC) performed at the time of a colposcopy. The indication for colposcopy was a Pap smear notable for atypical squamous cells of unknown significance, positive HPV. Initially conservative management was pursued, but given persistent atypia the patient ultimately decided to proceed with definitive management via hysterectomy. Final histologic assessment demonstrated an epithelioid trophoblastic tumor (ETT). This case highlights the unusual scenario of ETT presenting as atypical trophoblastic cells on endocervical curettage and the possible evolution of an atypical placental site nodule into an ETT.

Improved Prognosis of Treatment Failure in Cervical Cancer with Nontumor PET/CT Radiomics.

Radiomics has been applied to predict recurrence in several disease sites, but current approaches are typically restricted to analyzing tumor features, neglecting nontumor information in the rest of the body. The purpose of this work was to develop and validate a model incorporating nontumor radiomics, including whole-body features, to predict treatment outcomes in patients with previously untreated locoregionally advanced cervical cancer. Methods: We analyzed 127 cervical cancer patients treated definitively with chemoradiotherapy and intracavitary brachytherapy. All patients underwent pretreatment whole-body 18F-FDG PET/CT. To quantify effects due to the tumor itself, the gross tumor volume (GTV) was directly contoured on the PET/CT image. Meanwhile, to quantify effects arising from the rest of the body, the planning target volume (PTV) was deformably registered from each planning CT to the PET/CT scan, and a semiautomated approach combining seed-growing and manual contour review generated whole-body muscle, bone, and fat segmentations on each PET/CT image. A total of 965 radiomic features were extracted for GTV, PTV, muscle, bone, and fat. Ninety-five patients were used to train a Cox model of disease recurrence including both radiomic and clinical features (age, stage, tumor grade, histology, and baseline complete blood cell counts), using bagging and split-sample-validation for feature reduction and model selection. To further avoid overfitting, the resulting models were tested for generalization on the remaining 32 patients, by calculating a risk score based on Cox regression and evaluating the c-index (c-index > 0.5 indicates predictive power). Results: Optimal performance was seen in a Cox model including 1 clinical biomarker (whether or not a tumor was stage III-IVA), 2 GTV radiomic biomarkers (PET gray-level size-zone matrix small area low gray level emphasis and zone entropy), 1 PTV radiomic biomarker (major axis length), and 1 whole-body radiomic biomarker (CT bone root mean square). In particular, stratification into high- and low-risk groups, based on the linear risk score from this Cox model, resulted in a hazard ratio of 0.019 (95% CI, 0.004, 0.082), an improvement over stratification based on clinical stage alone, which had a hazard ratio of 0.36 (95% CI, 0.16, 0.83). Conclusion: Incorporating nontumor radiomic biomarkers can improve the performance of prognostic models compared with using only clinical and tumor radiomic biomarkers. Future work should look to further test these models in larger, multiinstitutional cohorts.

Positron Emission Tomography-Guided Bone Marrow-Sparing Radiation Therapy for Locoregionally Advanced Cervix Cancer: Final Results From the INTERTECC Phase II/III Trial.

PURPOSE: To test effects of positron emission tomography (PET)-based bone marrow-sparing (BMS) image-guided intensity modulated radiation therapy (IG-IMRT) on efficacy and toxicity for patients with locoregionally advanced cervical cancer. METHODS AND MATERIALS: In an international phase II/III trial, patients with stage IB-IVA cervical carcinoma were treated with either PET-based BMS-IG-IMRT (PET-BMS-IMRT group) or standard image-guided IMRT (IMRT group), with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy. The phase II component nonrandomly assigned patients to PET-BMS-IMRT or standard IMRT. The phase III trial randomized patients to PET-BMS-IMRT versus IMRT, with a primary endpoint of progression-free survival (PFS) but was closed early for futility. Phase III patients were analyzed separately and in combination with phase II patients, comparing acute hematologic toxicity, cisplatin delivery, PFS, overall survival (OS), and patterns of failure. In a post-hoc exploratory analysis, we investigated the association between pretreatment absolute lymphocyte count (ALC) and OS. RESULTS: In total, 101 patients were enrolled on the phase II/III trial, including 29 enrolled in phase III (PET-BMS-IMRT group: 16; IMRT group: 13) before early closure. Median follow-up was 33 months for phase III patients and 39 months for all patients. PFS and OS at 5 years for all patients were 73.6% (95% confidence interval [CI], 64.9%-84.3%) and 84% (95% CI, 76%-92.9%]), respectively. There were no differences in number of cisplatin cycles, OS, PFS, or patterns of failure between groups for the combined cohort. The incidence of acute grade ≥ 3 neutropenia was significantly lower in the PET-BMS-IMRT group compared with IMRT for randomized patients (19% vs 54%, χ2P = .048) and in the combined cohort (13% vs 35%, χ2P = .01). Patients with pretreatment ALC ≤ 1.5 k/µL had nonsignificantly worse OS on multivariable analysis (HR 2.85; 95% CI, 0.94-8.62; adjusted P = .216), compared with patients with ALC > 1.5 k/µL. There was no difference in posttreatment ALC by treatment group. CONCLUSIONS: PET-BMS-IMRT significantly reduced acute grade ≥3 neutropenia, but not treatment-related lymphopenia, compared with standard IMRT. We found no evidence that PET-BMS-IMRT affected chemotherapy delivery or long-term outcomes, and weak evidence of an association between pretreatment ALC and OS.

Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization: the PASTIME protocol.

BACKGROUND: Multidisciplinary care of placenta accreta spectrum cases improves pregnancy outcomes, but the specific components of such a multidisciplinary collaboration varies between institutions. As experience with placenta accreta spectrum increases, it is crucial to assess new surgical techniques and protocols to help improve maternal outcomes and to advocate for hospital resources. OBJECTIVE: This study aimed to assess a novel multidisciplinary protocol for the treatment of placenta accreta spectrum that comprises cesarean delivery, multivessel uterine embolization, and hysterectomy in a single procedure within a hybrid operative suite. STUDY DESIGN: This was a matched prepost study of placenta accreta spectrum cases managed before (2010-2017) and after implementation of the Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization protocol (2018-2021) at a tertiary medical center. Historical cases were managed with internal iliac artery balloon placement in selected cases with the decision to inflate the balloons intraoperatively at the discretion of the primary surgeon. Intraoperative Embolization cases were compared with historical cases in a 1:2 ratio matched on the basis of placenta accreta spectrum severity and surgical urgency. The primary outcome was a requirement for transfusion with packed red blood cells. Secondary outcomes included estimated surgical blood loss, operative and postoperative complications, procedural time, length of stay, and neonatal outcomes. RESULTS: A total of 15 Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization cases and 30 matched historical cases were included in the analysis. There were no demographic differences noted between the groups. A median (interquartile range) of 0 units (0-2 units) of packed red blood cells were transfused in the Intraoperative Embolization group compared with 2 units (0-4.5 units) in the historical group (P=.045); 5 of 15 (33.3%) Intraoperative Embolization cases required blood transfusions compared with 19 of 30 (63.3%) cases in the historical group (P=.11). The estimated blood loss was significantly less in the Intraoperative Embolization group with a median (interquartile range) of 750 mL (450-1050 mL) compared with 1750 mL (1050-2500 mL) in the historical group (P=.003). There were no cases requiring massive transfusion (≥10 red blood cell units in 24 hours) in the Intraoperative Embolization group compared with 5 of 30 (16.7%) cases in the historical group (P=.15). There were no intraoperative deaths from hemorrhagic shock using the Intraoperative Embolization protocol, whereas this occurred in 2 of the historical cases. The mean duration of the interventional radiology procedure was longer in the Intraoperative Embolization group (67.8 vs 34.1 minutes; P=.002). Intensive care unit admission and postpartum length of stay were similar, and surgical and postoperative complications were not significantly different between the groups. The gestational age and neonatal birthweights were similar; however, the neonatal length of stay was longer in the Intraoperative Embolization group (median duration, 32 days vs 15 days; P=.02) with a trend toward low Apgar scores. Incidence of arterial umbilical cord blood pH <7.2 and respiratory distress syndrome and intubation rates were not statistically different between the groups. CONCLUSION: A multidisciplinary pathway including a single-surgery protocol with multivessel uterine embolization is associated with a decrease in blood transfusion requirements and estimated blood loss with no increase in operative complications. The Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization protocol provides a definitive surgical method that warrants consideration by other centers specializing in placenta accreta spectrum treatment.

Clinical implications of plasma circulating tumor DNA in gynecologic cancer patients.

Molecular characterization of cancers is important in dictating prognostic factors and directing therapy. Next-generation sequencing of plasma circulating tumor DNA (ctDNA) offers less invasive, more convenient collection, and a more real-time representation of a tumor and its molecular heterogeneity than tissue. However, little is known about the clinical implications of ctDNA assessment in gynecologic cancer. We describe the molecular landscape identified on ctDNA, ctDNA concordance with tissue-based analysis, and factors associated with overall survival (OS) in gynecologic cancer patients with ctDNA analysis. We reviewed clinicopathologic and genomic information for 105 consecutive gynecologic cancer patients with ctDNA analysis, including 78 with tissue-based sequencing, enrolled in the Profile-Related Evidence Determining Individualized Cancer Therapy (NCT02478931) trial at the University of California San Diego Moores Cancer Center starting July 2014. Tumors included ovarian (47.6%), uterine (35.2%), cervical (12.4%), vulvovaginal (2.9%), and unknown gynecologic primary (1.9%). Most ovarian and uterine cancers (86%) were high grade. 34% (N = 17) of ovarian cancers had BRCA alterations, and 22% (N = 11) were platinum sensitive. Patients received median 2 (range 0-13) lines of therapy prior to ctDNA collection. Most (75.2%) had at least one characterized alteration on ctDNA analysis, and the majority had unique genomic profiles on ctDNA. Most common alterations were TP53 (N = 59, 56.2% of patients), PIK3CA (N = 26, 24.8%), KRAS (N = 14, 13.3%), BRAF (N = 10, 9.5%), ERBB2 (N = 8, 7.6%), and MYC (N = 8, 7.6%). Higher ctDNA maximum mutation allele frequency was associated with worse OS [hazard ratio (HR): 1.91, P = 0.03], while therapy matched to ctDNA alterations (N = 33 patients) was independently associated with improved OS (HR: 0.34, P = 0.007) compared to unmatched therapy (N = 28 patients) in multivariate analysis. Tissue and ctDNA genomic results showed high concordance unaffected by temporal or spatial factors. This study provides evidence for the utility of ctDNA in determining outcome and individualizing cancer therapy in patients with gynecologic cancer.

Phase II study of axalimogene filolisbac (ADXS-HPV) for platinum-refractory cervical carcinoma: An NRG oncology/gynecologic oncology group study.

OBJECTIVE: Women with persistent, recurrent, and/or metastatic cervical cancer have a poor prognosis. Even with the availability of cisplatin plus paclitaxel and bevacizumab, median overall survival (OS) is only 17.0 months, with median post-progression survival of approximately seven months. We studied the therapeutic vaccine, Axalimogene filolisbac (ADXS-HPV), in women who had progressed following at least one prior line of therapy (Gynecologic Oncology Group protocol 265/NCT01266460). METHODS: Volunteers ≥18 years with advanced cervical cancer and GOG performance status score of 0 or 1 were eligible for participation in this 2-stage, phase II trial. In stage 1, women received up to three doses of ADXS-HPV (1 × 109 colony-forming units in 250 mL IV over 15 min every 28 days) and were monitored for tumor progression. In stage 2, women were treated until progression, intolerable adverse events (AEs), or voluntary withdrawal of consent. Co-primary endpoints were safety and proportion of volunteers surviving ≥12 months. An estimated, combined (stages 1 + 2) 12-month OS of 35% was calculated from historical GOG cohorts to declare ADXS-HPV sufficiently active in this platinum-pre-treated population. Secondary endpoints were OS and progression-free survival (PFS). RESULTS: Among 50 evaluable volunteers, the 12-month OS was 38% (n = 19). Median OS was 6.1 months (95% CI: 4.3-12.1) and median PFS was 2.8 months (95% CI: 2.6-3.0). The most common treatment-related AEs were fatigue, chills, fever, nausea, and anemia. The majority of AEs were grade 1 or 2 and resolved spontaneously or with appropriate treatment. CONCLUSION: At the dose and schedule studied, ADXS-HPV immunotherapy was tolerable and met the protocol-specified benchmark for activity required to warrant further investigation in volunteers with cervical carcinoma.

Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms). We hypothesised that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer. METHODS: In this multicentre, open-label, randomised, phase 2 study, 11 different centres in the US Experimental Therapeutics Clinical Trials Network enrolled women (aged ≥18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of 0 or 1, who had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting. Eligible patients were randomly assigned (1:1) to receive intravenous gemcitabine (1000 mg/m2) on day 1 and day 8, or gemcitabine plus intravenous berzosertib (210 mg/m2) on day 2 and day 9 of a 21-day cycle until disease progression or intolerable toxicity. Randomisation was done centrally using the Theradex Interactive Web Response System, stratified by platinum-free interval, and with a permuted block size of six. Following central randomisation, patients and investigators were not masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival, and analyses included all patients who received at least one dose of the study drugs. The study is registered with ClinicalTrials.gov, NCT02595892, and is active but closed to enrolment. FINDINGS: Between Feb 14, 2017, and Sept 7, 2018, 88 patients were assessed for eligibility, of whom 70 were randomly assigned to treatment with gemcitabine alone (36 patients) or gemcitabine plus berzosertib (34 patients). At the data cutoff date (Feb 21, 2020), the median follow-up was 53·2 weeks (25·6-81·8) in the gemcitabine plus berzosertib group and 43·0 weeks (IQR 23·2-69·1) in the gemcitabine alone group. Median progression-free survival was 22·9 weeks (17·9-72·0) for gemcitabine plus berzosertib and 14·7 weeks (90% CI 9·7-36·7) for gemcitabine alone (hazard ratio 0·57, 90% CI 0·33-0·98; one-sided log-rank test p=0·044). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (14 [39%] of 36 patients in the gemcitabine alone group vs 16 [47%] of 34 patients in the gemcitabine plus berzosertib group) and decreased platelet count (two [6%] vs eight [24%]). Serious adverse events were observed in ten (28%) patients in the gemcitabine alone group and nine (26%) patients in the gemcitabine plus berzosertib group. There was one treatment-related death in the gemcitabine alone group due to sepsis and one treatment-related death in the gemcitabine plus berzosertib group due to pneumonitis. INTERPRETATION: To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting. FUNDING: US National Cancer Institute.

Phase 1 Trial of Concurrent Gemcitabine and Cisplatin with Image Guided Intensity Modulated Radiation Therapy for Locoregionally Advanced Cervical Carcinoma.

PURPOSE: The use of concurrent doublet chemotherapy with radiation for locoregionally advanced cervical cancer (LACC) is limited by gastrointestinal and hematologic toxicity. By reducing radiation dose to bowel and bone marrow, image guided intensity modulated radiation therapy (IG-IMRT) may improve chemotherapy tolerance. The goal of this study was to determine whether IG-IMRT could lead to improved tolerance to concurrent cisplatin and gemcitabine for LACC. METHODS AND MATERIALS: We conducted an open-label, nonrandomized, prospective phase 1 dose escalation trial at a tertiary academic cancer center (ClinicalTrials.gov identifier: NCT01554410). We enrolled patients with stage IB-IVA cervical cancer, with either an intact cervix or posthysterectomy with residual/recurrent pelvic or paraortic nodal involvement, undergoing radical pelvic or extended field chemoradiation therapy. Treatment consisted of chemoradiation with IG-IMRT (45-47.6 Gy, 25-28 fractions to the pelvis ± paraortic nodes with simultaneous nodal boost to 53.2-59.4 Gy, 28 fractions) plus 5 cycles of concurrent weekly cisplatin 40 mg/m2 with escalating doses of gemcitabine (50, 75, 100, or 125 mg/m2). Cohorts were separated preregistration according to whether the patient received pelvic or extended field IG-IMRT and whether gemcitabine followed (CG) or preceded (GC) cisplatin delivery. Dose-limiting toxicity (DLT) events were monitored up to 30 days after chemoradiation therapy. The primary endpoint was maximum tolerated dose (MTD) resulting in DLT probability ≤20%. RESULTS: Between February 2011 and June 2019, 35 patients were registered. Overall, 7 patients (20.0%) experienced DLTs. For the pelvic field cohort, the estimated MTD was 100 mg/m2 with GC sequencing, which is higher than the previously reported MTD for this regimen. The extended field cohort was closed after 2 of 3 patients experienced a DLT at the first dose level. CONCLUSIONS: IG-IMRT can permit higher doses of concurrent gemcitabine with cisplatin and pelvic radiation for LACC. However, acute toxicity remains a factor with this regimen, depending on radiation volume and chemotherapy sequencing.

The elevated risk of ovarian clear cell carcinoma among Asian Pacific Islander women in the United States is not affected by birthplace.

OBJECTIVE: To determine incidence of ovarian clear cell cancer (OCCC) by race ethnicity and how that relationship is affected by birthplace among Asian Pacific Islanders (API). METHODS: The 18 registries of the U.S. Surveillance, Epidemiology, and End Results (SEER) dataset were queried to identify all women registered with epithelial ovarian cancer from 1973 to 2013. Relative risks of OCCC to non-OCCC based on ethnicity and birthplace were compared. RESULTS: We identified 72, 501 women with epithelial ovarian cancer in the dataset; of these, 5078 (7.0%) had OCCC and 4859 (6.7%) were API. The age-adjusted incidence rate/100,000 women of OCCC was significantly higher in API women (0.6, 0.5-0.6 95% CI) compared to any other ethnicity. A significantly higher proportion of API women had OCCC (14.5%) compared to their White (6.6%, RR 2.2, p < 0.0001) and Black counterparts (4.3%, RR 3.4, p < 0.0001). The majority of API women were foreign-born (70.8%). The relative risk of clear cell compared to non-clear cell epithelial ovarian cancer was not demonstrably different among foreign born API women with ovarian cancer (RR 1.1, 95% CI 0.9 to 1.3, p = 0.6). CONCLUSIONS: We have demonstrated that, in the US, there is an elevated risk of OCCC associated with API ethnicity. Place of birth does not appear to significantly modify the association, suggesting that the increased risk of OCCC in API women may not be affected by acculturation or environmental exposure. Future research exploring the complex relationships between ethnicity and risk of malignancy will be important as we make progress in understanding disease process and treatment.

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.

Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-ß-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and ß-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance.

Molecular Imaging of endometrial sentinel lymph nodes utilizing fluorescent-labeled Tilmanocept during robotic-assisted surgery in a porcine model.

Molecular imaging with a fluorescent version of Tilmanocept may permit an accurate and facile detection of sentinel nodes of endometrial cancer. Tilmanocept accumulates in sentinel lymph nodes (SLN) by binding to a cell surface receptor unique to macrophages and dendritic cells. Four female Yorkshire pigs underwent cervical stromal injection of IRDye800-Tilmanocept, a molecular imaging agent tagged with near-infrared fluorescent dye and radiolabeled with gallium-68 and technetium-99m. PET/CT scans 1.5 hours post-injection provided pre-operative SLN mapping. Robotic-assisted lymphadenectomy was performed two days after injection, using the FireFly imaging system to identify nodes demonstrating fluorescent signal. After removal of fluorescent nodes, pelvic and periaortic node dissections were performed. Nodes were assayed for technetium-99m activity, and SLNs were established using the "10%-rule", requiring that the radioactivity of additional SLNs be greater than 10% of the "hottest" SLN. Thirty-four nodal samples were assayed ex vivo for radioactivity. All the SLNs satisfying the "10%-rule" were detected using the FireFly system. Five fluorescent nodes were detected, corresponding with preoperative PET/CT scan. Three pigs had one SLN and one pig had two SLNs, with 100% concordance between fluorescence and radioactivity. Fluorescent-labeled Tilmanocept permits real-time intraoperative detection of SLNs during robotic-assisted lymphadenectomy for endometrial cancer in a porcine model. When radiolabeled with gallium-68, Tilmanocept allows for preoperative localization of SLNs using PET/CT, and shows specificity to SLNs with persistent fluorescent signal, detectable using the FireFly system, for two days post-injection. In conclusion, these findings suggest that a phase I trial in human subjects is warranted, and that a long-term goal of an intra-operative administration of non-radioactive fluorescent-labeled Tilmanocept is possible.

A Novel PRKAR1B-BRAF Fusion in Gastrointestinal Stromal Tumor Guides Adjuvant Treatment Decision-Making During Pregnancy.

Gastrointestinal stromal tumors (GISTs) are rare in pregnancy, with only 11 reported cases. Adjuvant imatinib therapy, which targets the most common driver mutations in GIST (KIT and PDGFRA), is recommended for patients with high-risk GIST, but it has known teratogenicity in the first trimester. A 34-year-old G3P2 woman underwent exploratory laparotomy at 16 weeks' gestation for a presumed adnexal mass. Surgical findings included normal adnexa and a 14-cm solid small bowel mass. The mass was resected en bloc with a segment of jejunum followed by a primary anastomosis. Histopathology and genomic analyses demonstrated a GIST with high-risk features but lack of KIT/PDGFRA mutations and identified the presence of a previously unreported, pathogenic PRKAR1B-BRAF gene fusion. Given her tumor profile, adjuvant therapy with imatinib was not recommended. GIST is rare in pregnancy, but can masquerade as an adnexal mass in women of childbearing age. Because neoadjuvant/adjuvant imatinib has risks of teratogenicity, tumor molecular profiling is critical as we identified a previously unreported gene fusion of PRKAR1B with BRAF that is predicted to be imatinib-resistant. In this case, testing provided the rationale for not offering adjuvant imatinib to avoid unnecessary toxicity to the patient and fetus.

Survival of women with microinvasive adenocarcinoma of the cervix is not improved by radical surgery.

BACKGROUND: Treatment for early-invasive adenocarcinoma of the cervix remains controversial. Although data have shown similar survival rates to those seen with squamous cell carcinoma, conservative options for patients with microinvasive adenocarcinoma have not been as widely accepted. Despite comparable survival outcomes, patients with early-invasive adenocarcinoma are still routinely subjected to more radical surgical techniques than their equivalently staged squamous cell counterparts. OBJECTIVE: The objective of the study was to evaluate how less radical surgery has an impact on 5 year survival in patients with microinvasive adenocarcinoma of the cervix. STUDY DESIGN: The Surveillance, Epidemiology, and End Results database was queried from 1988 through 2010 to perform a retrospective analysis of women with International Federation of Gynecology and Obstetrics stage IA1 or IA2 cervical carcinoma. Five year survival by procedure type (local excision, simple hysterectomy, or radical hysterectomy) was determined for each cell type (squamous or adenocarcinoma), as was lymph node status. RESULTS: Among 1567 patients with cervical adenocarcinoma, 5 year survival was 97.3% (confidence interval, 95.8-98.2%) for stage IA1 disease and 98.3% (confidence interval, 96.5%, 99.2%) for stage IA2. For comparison, the 5-year survival rates for 5,749 patients with stage IAI or lA2 squamous cell carcinoma were 96.7% (confidence interval, 96.0-97.3%) and 95.6% (confidence interval, 94.4-96.5%), respectively. For stage IA1 ACA, survival was 96.6%, 98.4% and 96.5% following excision, hysterectomy and radical hysterectomy, respectively. For stage IA2 ACA, survival rates were 100%, 96.9% and 99.4%, respectively. There was no statistical difference in survival between patients having either cell type undergoing local excision (P = .26), simple hysterectomy (P = .08), or radical hysterectomy (P = .87). We also found no statistically significant difference in survival among patients with adenocarcinoma compared by treatment type (local excision compared with simple hysterectomy [P = .64]; local excision compared with radical hysterectomy [P = .82]; or simple hysterectomy compared with radical hysterectomy [P = .70]). Among patients with adenocarcinoma, 0.97% had positive pelvic lymph nodes, none had positive aortic lymph nodes, and 91.85% had confirmed negative lymph nodes. For squamous cell carcinoma, 0.72% of patients had positive pelvic lymph nodes and 0.10% had positive aortic lymph nodes. CONCLUSION: There was no significant difference in survival when patients were compared by cell type or procedure, suggesting that survival of patients with microinvasive adenocarcinoma is not improved by utilizing more invasive surgical methods. Regardless of histology, the frequency of nodal involvement was very low among both groups, supporting an overall excellent prognosis for all patients with microinvasive disease. We submit these data as evidence that preoperative planning of more conservative techniques is appropriate, not just for those with squamous histology or who desire future fertility, but for all patients with microinvasive cervical disease.

Longitudinal Changes in Active Bone Marrow for Cervical Cancer Patients Treated With Concurrent Chemoradiation Therapy.

PURPOSE: To quantify longitudinal changes in active bone marrow (ABM) distributions within unirradiated (extrapelvic) and irradiated (pelvic) bone marrow (BM) in cervical cancer patients treated with concurrent chemoradiation therapy (CRT). METHODS AND MATERIALS: We sampled 39 cervical cancer patients treated with CRT, of whom 25 were treated with concurrent cisplatin (40 mg/m2) and 14 were treated with cisplatin (40 mg/m2) plus gemcitabine (50-125 mg/m2) (C/G). Patients underwent 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and 1.5 to 6.0 months after treatment. ABM was defined as the subvolume of bone with standardized uptake value (SUV) above the mean SUV of the total bone. The primary aim was to measure the compensatory response, defined as the change in the log of the ratio of extrapelvic versus pelvic ABM percentage from baseline to after treatment. We also quantified the change in the proportion of ABM and mean SUV in pelvic and extrapelvic BM using a 2-sided paired t test. RESULTS: We observed a significant increase in the overall extrapelvic compensatory response after CRT (0.381; 95% confidence interval [CI]: 0.312, 0.449) and separately in patients treated with cisplatin (0.429; 95% CI: 0.340, 0.517) and C/G (0.294; 95% CI: 0.186, 0.402). We observed a trend toward higher compensatory response in patients treated with cisplatin compared with C/G (P=.057). Pelvic ABM percentage was reduced after CRT both in patients receiving cisplatin (P<.001) and in those receiving C/G (P<.001), whereas extrapelvic ABM percentage was increased in patients receiving cisplatin (P<.001) and C/G (P<.001). The mean SUV in pelvic structures was lower after CRT with both cisplatin (P<.001) and C/G (P<.001). The mean SUV appeared lower in extrapelvic structures after CRT in patients treated with C/G (P=.076) but not with cisplatin (P=.942). We also observed that older age and more intense chemotherapy regimens were correlated with a decreased compensatory response on multivariable analysis. In patients treated with C/G, mean pelvic bone marrow dose was found to be negatively correlated with the compensatory response. CONCLUSION: Patients have differing subacute compensatory responses after CRT, owing to variable recovery in unirradiated marrow. Intensive chemotherapy regimens appear to decrease the extrapelvic compensatory response, which may lead to increased hematologic toxicity.

Fertility preservation and survival among young women with early ovarian cancer living in US counties with gynecologic oncologist services.

OBJECTIVE: To examine the association between living in a county with gynecologic oncologist provision, the performance of fertility sparing surgery, and survival among young women with early epithelial ovarian cancer. METHODS: The present retrospective cohort study was based on the SEER 18 dataset of the US National Cancer Institute. Women younger than 45 years with early stage epithelial ovarian cancer diagnosed between 2000 and 2012 were included. Logistic regression and Cox proportional hazards methods were used to analyze all-cause survival. Adjustment was made for relevant clinical and demographic variables. RESULTS: In total, 1499 women were included. Women living in a county with gynecologic oncologist provision were less likely to undergo hysterectomy (adjusted odds ratio, 0.69; 95% confidence interval, 0.52-0.93) at the time of primary surgery. Women who underwent hysterectomy had a similar risk of mortality as women with uterine preservation (adjusted hazard ratio [HR], 0.73; 95% CI, 0.41-1.30). Living in a county with gynecologic oncologist provision was associated with reduced risk of mortality (adjusted HR, 0.53; 95% CI, 0.31-0.92). CONCLUSION: Living in a county with gynecologic oncologist provision was independently associated with the use of fertility sparing surgery among young women with early epithelial ovarian cancer.

Bone Marrow-sparing Intensity Modulated Radiation Therapy With Concurrent Cisplatin For Stage IB-IVA Cervical Cancer: An International Multicenter Phase II Clinical Trial (INTERTECC-2).

PURPOSE: To test the hypothesis that intensity modulated radiation therapy (IMRT) reduces acute hematologic and gastrointestinal (GI) toxicity for patients with locoregionally advanced cervical cancer. METHODS AND MATERIALS: We enrolled patients with stage IB-IVA cervical carcinoma in a single-arm phase II trial involving 8 centers internationally. All patients received weekly cisplatin concurrently with once-daily IMRT, followed by intracavitary brachytherapy, as indicated. The primary endpoint was the occurrence of either acute grade ≥3 neutropenia or clinically significant GI toxicity within 30 days of completing chemoradiation therapy. A preplanned subgroup analysis tested the hypothesis that positron emission tomography-based image-guided IMRT (IG-IMRT) would lower the risk of acute neutropenia. We also longitudinally assessed patients' changes in quality of life. RESULTS: From October 2011 to April 2015, 83 patients met the eligibility criteria and initiated protocol therapy. The median follow-up was 26.0 months. The incidence of any primary event was 26.5% (95% confidence interval [CI] 18.2%-36.9%), significantly lower than the 40% incidence hypothesized a priori from historical data (P=.012). The incidence of grade ≥3 neutropenia and clinically significant GI toxicity was 19.3% (95% CI 12.2%-29.0%) and 12.0% (95% CI 6.7%-20.8%), respectively. Compared with patients treated without IG-IMRT (n=48), those treated with IG-IMRT (n=35) had a significantly lower incidence of grade ≥3 neutropenia (8.6% vs 27.1%; 2-sided χ2P=.035) and nonsignificantly lower incidence of grade ≥3 leukopenia (25.7% vs 41.7%; P=.13) and any grade ≥3 hematologic toxicity (31.4% vs 43.8%; P=.25). CONCLUSIONS: IMRT reduces acute hematologic and GI toxicity compared with standard treatment, with promising therapeutic outcomes. Positron emission tomography IG-IMRT reduces the incidence of acute neutropenia.

Diagnosis and treatment of Clostridium difficile (C. diff) colitis: Review of the literature and a perspective in gynecologic oncology.

Clostridium difficile infection (CDI) is a major cause of nosocomial diarrhea with the potential for significant morbidity and mortality. Colonization in a susceptible individual, with risk factors such as prior antibiotic use, advanced age, or medical comorbidities, may result in symptomatic infection. Although patients with a gynecologic malignancy may be at a higher risk of developing CDI due to an increased likelihood of having one or more risk factors, data do not consistently support the idea that chemotherapy or cancer itself are independently associated with CDI. For diagnosis of CDI, we recommended using a multi-step approach, with a highly sensitive initial rapid test such as the enzyme immunoassay (EIA) for glutamate dehydrogenase (GDH) or nucleic acid amplification testing (NAAT), followed by confirmatory testing with of the above two tests or EIA toxin A/B, which has high specificity. Treatment varies based on the severity of disease. We recommend vancomycin as first-line therapy for an initial episode of mild/moderate or severe CDI, with consideration of fidaxomicin for patients at particularly high risk for recurrence. Rectal vancomycin may play an adjunctive role for some severe cases, while surgical intervention is indicated for fulminant CDI if no improvement six or more days after initiating medical therapy. For non-severe recurrent disease, the initial treatment regimen should be repeated, while subsequent episodes are more appropriately treated with a tapered and pulsed dose of vancomycin, fidaxomicin, or fecal microbiota transplantation.

Squamous Cell Carcinoma of the Vulva Presenting as an Isolated Inguinal Lymph Node Metastasis: A Case Report.

Background: Vulvar carcinoma is usually diagnosed after a patient notices bleeding, pruritis, or a lesion. We describe a case of vulvar carcinoma presenting as an isolated lymph node metastasis in the setting of negative pelvic examinations, with interval development of a vulvar lesion. Case: A 45-year-old woman presented with a left groin mass, and a biopsy revealed squamous cell carcinoma of unknown primary. She underwent an extensive work-up including several evaluations by gynecologic oncologists, all with negative results. Only after 11 months of clinical monitoring did a vulvar lesion appear and the primary tumor was diagnosed. Conclusion: Cancers of unknown primary site presenting in an inguinal lymph node are relatively rare. Vulvar carcinoma should remain in the differential diagnosis even in the setting of a previously negative pelvic examination.

Urinary diversions: A time to enrich surgical training?

OBJECTIVE: To assess the potential exposure to complex urologic procedures, specifically urinary diversion, during a gynecologic oncology fellowship. METHODS: We queried the University HealthSystem Consortium (UHC) database to determine the total number of urinary diversions performed from October 2008 to August 2012. This data was used to estimate the mean number of urinary diversions performed each year. Gender, primary diagnosis, type of diversion, gynecologic oncologist involvement, and medical center were explored. RESULTS: Of the nearly 21,000 urinary diversions performed in UHC participating hospitals during the study period, 6180 (29.5%) were performed in women. On average, 1648 urinary diversions are performed in women each year, with gynecologic malignancies accounting for 6.8% of cases. We estimate that a gynecologic oncologist was involved with 87 cases per year at nonprofit academic medical centers in the US. With approximately 112 clinically active fellows per year during the study period, this equates to less than one diversion per clinical fellow per year if cases are equally distributed among centers. However, the majority of urinary diversions with gynecologic oncologist involvement were performed at just a fraction of centers. Thus, only a small contingent of fellows may be getting the greatest exposure to urinary diversions. CONCLUSIONS: The majority of urinary diversions in women in the US are performed for bladder carcinoma by urologists. The estimated number of cases per clinical gynecologic oncology fellow per year is less than one. Strategies to improve fellow exposure to urinary diversion and consideration of alternative surgical training modalities should be explored.

Clinical Outcomes of Computed Tomography-Based Volumetric Brachytherapy Planning for Cervical Cancer.

PURPOSE/OBJECTIVES: A report of clinical outcomes of a computed tomography (CT)-based image guided brachytherapy (IGBT) technique for treatment of cervical cancer. METHODS AND MATERIALS: Seventy-six women with International Federation of Gynecology and Obstetrics stage IB to IVA cervical carcinoma diagnosed between 2007 and 2014 were treated with definitive external beam radiation therapy (EBRT) with or without concurrent chemotherapy followed by high-dose-rate (HDR) IGBT. All patients underwent planning CT simulation at each implantation. A high-risk clinical target volume (HRCTV) encompassing any visible tumor and the entire cervix was contoured on the simulation CT. When available, magnetic resonance imaging (MRI) was performed at implantation to assist with tumor delineation. The prescription dose was prescribed to the HRCTV. RESULTS: The median follow-up time was 17 months. Thirteen patients (17%) had an MRI done before brachytherapy, and 16 patients (21%) were treated without MRI guidance. The mean EBRT/IGBT sum 2-Gy equivalent dose (EQD2) delivered to the 90% volume of the HRCTV was 86.3 Gy. The mean maximum EQD2s delivered to 2 cm(3) of the rectum, sigmoid, and bladder were 67.5 Gy, 66.2 Gy, and 75.3 Gy, respectively. The 2-year cumulative incidences of local, locoregional, and distant failure were 5.8% (95% confidence interval [CI]: 1.4%-14.8%), 15.1% (95% CI: 5.4%-29.4%), and 24.3% (95% CI: 12.1%-38.9%), respectively. The 2-year overall and disease-free survival rates were 75% (95% CI, 61%-91%) and 73% (95% CI, 60%-90%), respectively. Twenty-nine patients (38%) experienced grade ≥ 2 acute toxicity, with 5 cases of acute grade 3 toxicity and no grade ≥ 4 toxicities. One patient experienced grade 3 gastrointestinal toxicity. No other late grade ≥ 3 events were observed. CONCLUSIONS: This is the largest report to date of CT/MRI-based IGBT for the treatment of cervical cancer. The results are promising, with excellent local control and acceptable toxicity. Further investigation is needed to assess the long-term safety and efficacy of this treatment.