Carcinomatosis in Early-Stage Cervical Cancer Treated with Robotic Radical Hysterectomy: Recurrence Patterns, Risk Factors, and Survival.

PURPOSE: Minimally invasive radical hysterectomy has been associated with increased recurrence of disease and worse survival compared with open radical hysterectomy for early-stage cervical cancer. We evaluated patterns of recurrence and histopathologic risk factors in patients who underwent robotic radical hysterectomy (RRH). METHODS: Patients who underwent RRH (4/2007-12/2018) were evaluated for specific locations of recurrent disease, disease-free survival, overall survival (OS), and histopathologic risk factors for recurrence. Inclusion criteria were follow-up ≥ 1 year, histology with adenocarcinoma, adenosquamous, or squamous carcinoma and clinical stage IA2 to IB ≤ 4-cm tumor size cervical cancers (FIGO-2018). RESULTS: A total of 140 patients underwent RRH and 112 met criteria. Median tumor size was 2.1 cm [interquartile range (IQR): 1.1-3.3]. Median follow-up was 61 months (IQR: 36-102). Fifty (45%) patients underwent adjuvant radiation ± cisplatin with either Sedlis' or Peters' risk factors. There were 11 (9.8%) recurrences with median disease-free survival of 12 (IQR 8.5) months. All patients with recurrence had measured tumor size ≥ 2 cm (median tumor size 3-cm (IQR: 2.6-4.0). Tumor size > 2 cm was associated with Sedlis' intermediate-risk factors (p < 0.05) and Peters' high-risk factors (p < 0.05). Forty patients underwent preoperative conization, and two (5%) with deep positive margins in lesions > 2 cm recurred. Five (4.5%) of patients had carcinomatosis representing 45% of all recurrences. Carcinomatosis was associated with reduced OS compared with other recurrence patterns (22 months vs. 7.8 years, p < 0.05). CONCLUSIONS: Carcinomatosis was observed in early-stage cervical cancers treated with RRH and was associated with reduced OS. All recurrences were associated with lesions ≥ 2 cm, and no recurrences were identified with negative conization margins.

A phase 1b study of intraperitoneal oncolytic viral immunotherapy in platinum-resistant or refractory ovarian cancer.

OBJECTIVE: Our objective was to assess safety and adverse events associated with intraperitoneal Olvi-Vec virotherapy in patients with platinum-resistant or refractory ovarian cancer (PRROC). Secondary objectives included objective response rate (ORR) per RECIST 1.1 and progression-free survival (PFS). METHODS: Olvi-Vec is a modified vaccinia virus that causes oncolysis and immune activation. An open-label phase 1b trial using a 3 + 3 dose escalation was conducted. Intraperitoneal Olvi-Vec was given as monotherapy in two consecutive daily doses. Translational analyses included anti-virus antibody levels, viral shedding, circulating tumor cells (CTCs) and T cells. RESULTS: Twelve patients (median age: 69 years, range: 45-77) with median 5 prior therapies (range: 2-10) and 2 prior platinum lines (range: 1-5) were enrolled. There were three dose level cohorts: 3 × 109 (n = 6), 1 × 1010 (n = 5), and 2.5 × 1010 (n = 1) plaque forming units (PFU)/day on two consecutive days. Treatment-related adverse events (TRAEs) included G1/G2 nausea (n = 6), fever (n = 6), abdominal distention (n = 5), and abdominal pain (n = 4). There were no Grade 4 TRAEs, no dose relationship to TRAEs, and no deaths attributed to Olvi-Vec. The ORR was 9% (1/11). Stable disease (SD) was 64% (7/11), and SD ≥15 weeks was 46% (5/11). Median PFS was 15.7 weeks (95%CI: 5.7-34.5), including extended PFS in four patients (23.2, 34.5, 59.4+ and 70.8 weeks). Three patients had extended overall survival (deceased 33.6 months, and alive with disease at 54 and 59 months). CTCs diminished in 6/8 (75%) baseline-positive patients. Immune activation was demonstrated from virus-enhanced tumor infiltration of CD8+ T-cells and activation of tumor-specific T-cells in peripheral blood. CONCLUSIONS: Oncolytic viral therapy with intraperitoneal Olvi-Vec showed promising safety, clinical activities, and immune activation in patients with PRROC, warranting further clinical investigation.

Placental SARS-CoV-2 in a pregnant woman with mild COVID-19 disease.

The full impact of coronavirus disease 2019 (COVID-19) on pregnancy remains uncharacterized. Current literature suggests minimal maternal, fetal, and neonatal morbidity and mortality. COVID-19 manifestations appear similar between pregnant and nonpregnant women. We present a case of placental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in a woman with mild COVID-19 disease, then review the literature. Reverse transcriptase polymerase chain reaction was performed to detect SARS-CoV-2. Immunohistochemistry staining was performed with specific monoclonal antibodies to detect SARS-CoV-2 antigen or to identify trophoblasts. A 29-year-old multigravida presented at 40-4/7 weeks for labor induction. With myalgias 2 days prior, she tested positive for SARS-CoV-2. We demonstrate maternal vascular malperfusion, with no fetal vascular malperfusion, as well as SARS-CoV-2 virus in chorionic villi endothelial cells, and also rarely in trophoblasts. To our knowledge, this is the first report of placental SARS-CoV-2 despite mild COVID-19 disease (no symptoms of COVID-19 aside from myalgias); patient had no fever, cough, or shortness of breath, but only myalgias and sick contacts. Despite her mild COVID-19 disease in pregnancy, we demonstrate placental vasculopathy and presence of SARS-CoV-2 virus across the placenta. Evidence of placental COVID-19 raises concern for placental vasculopathy (potentially leading to fetal growth restriction and other pregnancy complications) and possible vertical transmission-especially for pregnant women who may be exposed to COVID-19 in early pregnancy. This raises important questions of whether future pregnancy guidance should include stricter pandemic precautions, such as screening for a wider array of COVID-19 symptoms, increased antenatal surveillance, and possibly routine COVID-19 testing throughout pregnancy.

Robotic sentinel lymph node (SLN) mapping in endometrial cancer: SLN symmetry and implications of mapping failure.

PURPOSE: To establish the bilateral pelvic concordance rate of the sentinel lymph node (SLN) and determine the likelihood of lymph node metastasis in cases of mapping failure. METHODS: A database analysis was performed on 414 patients with clinical stage I endometrial cancer who underwent SLN mapping followed by robotic hysterectomy and completion pelvic (n=414, 100%) and aortic (n=186, 44.9%) lymphadenectomy from March 2011 to August 2016. Stage, histology, SLN sites, and surgico-pathologic findings were analyzed. The bilateral concordance rate of SLN location, successful unilateral and bilateral mapping rates, false negative rate, and non-SLN metastasis associated with mapping failure were calculated. RESULTS: Histologies included 354 (85.5%) endometrioid, 39 (9.4%) serous, 16 (3.9%) carcinosarcoma, 4 (1.0%) clear cell, and 1 (0.2%) undifferentiated. Final stages included 262 (63.3%) IA, 36 (8.7%) IB, 15 (3.6%) II, 6 (1.4%) IIIA, 68 (16.4%) IIIC1, and 27 (6.5%) IIIC2. Bilateral SLN mapping was successful in 355 (85.7%) patients, and 266 (74.9%) demonstrated mapping to the symmetrical lymphatic group contralaterally. The mapping failure rate was 13.5% (56/414) unilaterally and 0.7% (3/414) bilaterally. SLN locations were external iliac (69.1%), obturator (25.1%), internal iliac (2.2%), common iliac (1.9%), pre-sacral (0.9%), aortic (0.4%), parametrial (0.3%), and para-rectal (0.1%). Lymph node metastases were identified in 95 (22.9%) pelvic and 27 (6.5%) aortic nodes. 10 (16.9%) cases with mapping failure had lymph node metastasis on completion lymphadenectomy, similar to the proportion of SLNs with metastases (p=0.35). However, macro-metastases were more common in mapping failure completion lymphadenectomies than in the positive SLNs (80% vs 22.3%, p<0.001). CONCLUSION: The contralateral SLN location concordance rate was 75%. Most SLNs were along the medial external iliac or obturator locations. The rate of positive lymph nodes associated with SLN mapping failure was 16.9%, similar to the overall node-positive rate. The detection of pelvic node metastasis with SLN mapping failure was largely populated with macro-metastases and confirms the necessity of completion lymphadenectomy with mapping failure.

Widespread choriocarcinoma metastases from de-differentiated gastro-esophageal junction primary adenocarcinoma: A case report with literature review.

BACKGROUND: Non-gestational choriocarcinomas represent a small subset of germ cell tumors. The majority of non-gestational choriocarcinomas arise from the gynecologic tract. In rare cases, they can originate from other sites, and very few such cases have been reported in peer-reviewed literature. We add to this small collection with an interesting case of non-gestational choriocarcinoma arising from a primary gastrointestinal adenocarcinoma. CASE PRESENTATION: A 62-year-old female presented to the emergency department with ocular hemorrhage. Originally thought to have melanoma, full-body computed tomography (CT) revealed widespread metastases including a 3 cm hemorrhagic brain mass, hepatic metastases, and a mass at the gastro-esophageal (GE) junction. Pathology of the intracranial mass revealed a malignant neoplasm consistent with choriocarcinoma. Recent dilation and curettage (D&C) were negative for malignancy. Esophagogastroduodenoscopy (EGD) biopsy of the GE junction mass showed poorly differentiated adenocarcinoma, likely the primary lesion, while the liver biopsy matched the ß-hCG staining pattern as seen in the brain. CONCLUSIONS: Choriocarcinomas can rarely originate outside of the female reproductive tract (non-gestational, primary choriocarcinomas). In the infrequent cases where a gestational origin is clinically unlikely, the differential diagnosis includes a non-gestational primary choriocarcinoma and choriocarcinomatous differentiation in another primary malignancy. Careful correlation with imaging and clinico-pathologic studies is paramount to determining their origin and guiding further clinical treatment.

Sentinel lymph nodes (SLN) in endometrial cancer: The relationship between primary tumor histology, SLN metastasis size, and non-sentinel node metastasis.

OBJECTIVES: To examine sentinel lymph node pathology and describe relationships to uterine pathology, non-sentinel pelvic lymph nodes, and para-aortic lymph nodes. METHODS: Patients with apparent uterine-confined endometrial cancer underwent robotic hysterectomy, SLN mapping, completion pelvic lymphadenectomy (LND), and para-aortic (PaLND) directed by frozen section. Patients were risk stratified by histology: low-risk (LR) endometrioid <50% depth-of-invasion (DOI), intermediate-risk (IR) endometrioid ≥50% DOI, and high-risk (HR) type II histology for comparison to other pelvic/aortic metastases. RESULTS: 414 patients were stratified: 275 LR, 80 IR, and 59 HR cases. PaLND was performed in 84.2% of IR/HR patients and 25.1% LR patients. Pelvic node metastasis was detected in 11.6% LR, 50.0% IR, and 39.0% HR patients. PaLN metastasis was detected in 2.9% LR, 11.3% IR, and 16.9% HR patients. Proportionally, isolated tumor cells (ITC) SLNs were more common in LR or IR vs. HR group (51.6% and 44.7% vs. 15.0%, p < 0.05). The SLN false negative rates (FNR) were 0% LR, 2.5% IR, and 5.1% HR. Non-sentinel pelvic node metastases were present in 28(31.5%) of all SLN+ cases, but only 3(8.3%) of SLN with ITC. PaLN metastasis was found in 18.8% LR, 11.8% IR, and 33.3% HR cases with ITC SLNs. After controlling for DOI, LVSI, and grade, ITC-positive SLNs had a significant association with non-sentinel pelvic and aortic metastasis (p = 0.03 and p = 0.008, respectively). CONCLUSIONS: Patients with HR histology have more micro/macro-metastases in both SLNs and non-SLN metastases compared to LR/IR patients. SLN ITCs were associated with a clinically significant incidence of PaLN metastasis across all histology risk groups. There were no cases of isolated aortic node metastasis in this study. SLN mapping had an increased, although clinically acceptable FNR in the HR cohort compared to LR patients.

Abnormal oxidative stress responses in fibroblasts from preeclampsia infants.

BACKGROUND: Signs of severe oxidative stress are evident in term placentae of infants born to mothers with preeclampsia (PE), but it is unclear whether this is a cause or consequence of the disease. Here fibroblast lines were established from umbilical cords (UC) delivered by mothers who had experienced early onset PE and from controls with the goal of converting these primary cells to induced pluripotent stem cells and ultimately trophoblast. Contrary to expectations, the oxidative stress responses of these non-placental cells from PE infants were more severe than those from controls. METHODS AND FINDINGS: Three features suggested that UC-derived fibroblasts from PE infants responded less well to oxidative stressors than controls: 1) While all UC provided outgrowths in 4% O2, success was significantly lower for PE cords in 20% O2; 2) PE lines established in 4% O2 proliferated more slowly than controls when switched to 20% O2; 3) PE lines were more susceptible to the pro-oxidants diethylmaleate and tert-butylhydroquinone than control lines, but, unlike controls, were not protected by glutathione. Transcriptome profiling revealed only a few genes differentially regulated between PE lines and controls in 4% O2 conditions. However, a more severely stressed phenotype than controls, particularly in the unfolded protein response, was evident when PE lines were switched suddenly to 20% O2, thus confirming the greater sensitivity of the PE fibroblasts to acute changes in oxidative stress. CONCLUSIONS: UC fibroblasts derived from PE infants are intrinsically less able to respond to acute oxidative stress than controls, and this phenotype is retained over many cell doublings. Whether the basis of this vulnerability is genetic or epigenetic and how it pertains to trophoblast development remains unclear, but this finding may provide a clue to the basis of the early onset, usually severe, form of PE.

Antichlamydial antibodies, human fertility, and pregnancy wastage.

Genital infections with Chlamydia trachomatis (C. trachomatis) continue to be a worldwide epidemic. Immune response to chlamydia is important to both clearance of the disease and disease pathogenesis. Interindividual responses and current chlamydial control programs will have enormous effects on this disease and its control strategies. Humoral immune response to C. trachomatis occurs in humans and persistent antibody levels appear to be most directly correlated with more severe and longstanding disease and with reinfection. There is a close correlation between the presence of antichlamydial antibodies in females and tubal factor infertility; the closest associations have been found for antibodies against chlamydial heat shock proteins. The latter antibodies have also been shown to be useful among infertile patients with prior ectopic pregnancy, and their presence has been correlated with poor IVF outcomes, including early pregnancy loss. We review the existing literature on chlamydial antibody testing in infertile patients and present an algorithm for such testing in the infertile couple.