Risk of second primary cancers among survivors of gynecological cancers.

OBJECTIVE: Survivors of gynecologic cancers have an increased risk of developing second primary cancers (SPC); however it is unclear which sites have higher risks. We aimed to ascertain risk of SPC among survivors of gynecological cancer, and identify anatomic sites at risk of SPC. METHODS: We queried the Surveillance, Epidemiology and End Results database (2000-2016) for confirmed cases of index gynecological (cervix uteri [cervical], corpus and uterus [endometrial], ovarian, vaginal, and vulvar) cancers. Risk of SPC was estimated using standardized incidence ratios (SIRs: observed/expected cases) and excess absolute risks (EARs: observed - expected cases) per 10,000 person-years at risk (PYR). SIRs and EARs were stratified by index anatomic site and latency interval. RESULTS: Among the cohort of 301,210 gynecological cancer survivors, 19,005 (6.31%) developed an SPC (SIR = 1.16; 95% CI, 1.15-1.18 and EAR = 17.2 cases per 10,000 PYR) compared with the general population. All gynecological cancer survivors (except survivors of ovarian) had a significant risk of developing SPC (SIR range 1.06-2.16), with survivors of vulvar cancer having the highest risk (SIR = 2.16; 95% CI, 2.06-2.27; EAR = 139.5 per 10,000 PYR). Risk of SPC was highest within the first 5 years post-diagnosis for survivors of cervical, vulvar and vaginal cancers. CONCLUSIONS: While most index gynecological cancer sites are associated with increased risk of SPC, risk is highest among survivors of vulvar cancer. These findings have the potential to inform lifelong surveillance recommendations for gynecological cancer survivors.

Non-steroidal anti-inflammatory agents to induce regression and prevent the progression of cervical intraepithelial neoplasia.

BACKGROUND: This is an updated version of the original Cochrane review published in 2014, Issue 4. Cervical intraepithelial neoplasia (CIN) precedes the development of invasive carcinoma of the cervix. Current treatment of CIN is quite effective, but there is morbidity for the patient related to pain, bleeding, infection, cervical stenosis and premature birth in a subsequent pregnancy. Effective treatment with medications, rather than surgery, would be beneficial. OBJECTIVES: To evaluate the effectiveness and safety of non-steroidal anti-inflammatory agents (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, to induce regression and prevent the progression of CIN. SEARCH METHODS: Previously, we searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 11), MEDLINE (November, 2013) and Embase (November week 48, 2013). An updated search was performed in August 2017 for CENTRAL (2017, Issue 8), MEDLINE (July, week 3, 2017) and Embase (July week 31, 2017). Trial registries and journals were also searched as part of the update. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled trials of NSAIDs in the treatment of CIN. DATA COLLECTION AND ANALYSIS: Three review authors independently abstracted data and assessed risks of bias in accordance with Cochrane methodology. Outcome data were pooled using fixed-effect meta-analyses. MAIN RESULTS: In three RCTs, 171 women over the age of 18 years were randomised to receive celecoxib 400 mg daily for 14 to 18 weeks versus placebo (one study, 130 participants), celecoxib 200 mg twice daily by mouth for six months versus placebo (one study, 25 participants), or rofecoxib 25 mg once daily by mouth for three months versus placebo (one study, 16 participants). The study with rofecoxib was discontinued when the medicine was withdrawn from the market in 2004. The trials ran from June 2005 to April 2012, June 2002 to October 2003, and May to October 2004, respectively. We have chosen to include the data from the rofecoxib study as outcomes may be similar when other such NSAIDs are utilised.Partial or complete regression of CIN 2 or CIN 3 occurred in 31 out of 70 (44%) in the treatment arms and 19 of 62 (31%) in the placebo arms (risk ratio (RR) 1.45, 95% confidence interval (CI) 0.93 to 2.27; P value 0.10), three studies, 132 participants; moderate-certainty evidence). Complete regression of CIN 2 or CIN 3 occurred in 15 of 62 (24%) of those receiving celecoxib versus 10 of 54 (19%) of those receiving placebo (RR 1.31, 95% CI 0.65 to 2.67; P value 0.45, two studies, 116 participants; moderate-certainty evidence). Partial regression of CIN 2 or CIN 3 occurred in 14 of 62 (23%) of those receiving celecoxib versus 8 of 54 (15%) of those receiving placebo (RR 1.56, 95% CI 0.72 to 3.4; P value 0.26), two studies, 116 participants; moderate-certainty evidence).Progression to a higher grade of CIN, but not to invasive cancer, occurred in one of 12 (8%) of those receiving celecoxib and two of 13 (15%) receiving placebo (RR 0.54, 95% CI 0.05 to 5.24; P value 0.60, one study, 25 participants; very low-certainty evidence). Two studies reported no cases of progression to invasive cancer within the timeframe of the study. No toxicity was reported in the two original articles. The trial added in this update had one Grade 3 gastrointestinal adverse effect in the treatment arm, but otherwise had similar Grade 1 to 2 side effects between treatment and placebo groups. Although the studies were well-conducted and randomised, some risk of bias was detected in all studies. Furthermore, the duration of the studies was short, which may mask identifying progression to cancer.The addition of the trial in this update quadrupled the number of patients in the original review and was a well-designed multicentre trial thus, increasing the overall certainty of evidence from very low to moderate for this review. AUTHORS' CONCLUSIONS: There are currently no convincing data to support a benefit for NSAIDs in the treatment of CIN. With the addition of this new, larger randomised trial we would rate this as overall moderate-certainty evidence by the GRADE criteria.

Multiplex profiling identifies distinct local and systemic alterations during intraperitoneal chemotherapy for ovarian cancer: An NRG Oncology/Gynecologic Oncology Group Study.

OBJECTIVES: Ovarian cancer leads to abdominal carcinomatosis and late stage (III/IV) diagnosis in 75% of patients. Three randomized phase III trials have demonstrated that intraperitoneal (IP) chemotherapy improves outcomes in epithelial ovarian cancer. While IP treatment is validated by clinical trials, there is a poor understanding of the mechanism(s) leading to the survival advantage other than the increased concentration of cytotoxic drugs within the tumor microenvironment. A better understanding of this process through analysis of dynamic biomarkers should promote novel approaches that may enhance tumor clearance. We propose this pilot study to confirm the feasibility of collecting serial peritoneal samples from implanted catheters in women receiving IP chemotherapy. We believe these specimens may be used for multiplex analysis to reveal unique biomarker fluctuations when compared to peripheral blood. METHODS: From 13 women participating on GOG 252, 30 whole blood, 12 peritoneal fluid (PF), and 20 peritoneal wash (PW) with 30mL saline were obtained. Samples were requested prior to the first three chemotherapy cycles. Samples were assessed for volume, cell populations, protein, RNA, and miRNA content changes. RESULTS: Median volume for PF was 1.6mL and 3.1mL for PW. PW is a dilution of PF capable of capturing measurable biomarkers. Peritoneal aspirates contain a unique profile of biomarkers distinct from blood. miRNA undergo earlier alteration with chemotherapy than genes. Flow cytometry does not adequately capture biomarker fluctuations. CONCLUSIONS: As a proof of principle study, this trial provides evidence that sampling the peritoneal cavity can be adapted for biomarker analysis.

Anti-PD-L1 prolongs survival and triggers T cell but not humoral anti-tumor immune responses in a human MUC1-expressing preclinical ovarian cancer model.

Monoclonal antibodies that block inhibitory immune checkpoint molecules and enhance anti-tumor responses show clinical promise in advanced solid tumors. Most of the preliminary evidence on therapeutic efficacy of immune checkpoint blockers comes from studies in melanoma, lung and renal cancer. To test the in vivo potential of programmed death-ligand 1 (PD-L1) blockade in ovarian cancer, we recently generated a new transplantable tumor model using human mucin 1 (MUC1)-expressing 2F8 cells. The MUC1 transgenic (MUC1.Tg) mice develop large number of intraperitoneal (IP) tumors following IP injection of 8 × 10(5) syngeneic 2F8 cells. The tumors are aggressive and display little T cell infiltration. Anti-PD-L1 antibody was administered IP every 2 weeks (200 µg/dose) for a total of three doses. Treatment was started 21 days post-tumor challenge, a time point which corresponds to late tumor stage. The anti-PD-L1 treatment led to substantial T cell infiltration within the tumor and significantly increased survival (p = 0.001) compared to isotype control-treated mice. When the same therapy was administered to wild-type mice challenged with 2F8 tumors, no survival benefit was observed, despite the presence of high titer anti-MUC1 antibodies. However, earlier treatment (day 11) and higher frequency of IP injections restored the T cell responses and led to prolonged survival. Splenocyte profiling via Nanostring using probes for 511 immune genes revealed a treatment-induced immune gene signature consistent with increased T cell-mediated immunity. These findings strongly support further preclinical and clinical strategies exploring PD-L1 blockade in ovarian cancer.

Non-steroidal anti-inflammatory agents to induce regression and prevent the progression of cervical intraepithelial neoplasia.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) precedes the development of invasive carcinoma of the cervix. Current treatment of CIN is quite effective, but there is morbidity for the patient related to pain, bleeding, infection, cervical stenosis and premature birth in subsequent pregnancy. Effective treatment with medications, rather than surgery, would be beneficial. OBJECTIVES: To evaluate the effectiveness and safety of non-steroidal anti-inflammatory agents (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, to induce regression and prevent the progression of cervical intraepithelial neoplasia CIN. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11, 2013), MEDLINE (November, 2013) and EMBASE (November week 48, 2013). We also searched abstracts of scientific meetings and reference lists of included studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled trials of NSAIDs in the treatment of CIN. DATA COLLECTION AND ANALYSIS: Three review authors independently abstracted data and assessed risks of bias. Outcome data were pooled using random-effects meta-analyses. MAIN RESULTS: In two RCTs, 41 women over the age of 18 years, in an outpatient setting, were randomised to receive celecoxib 200 mg twice daily by mouth for six months versus placebo (one study, 25 participants) or rofecoxib 25 mg once daily by mouth for three months versus placebo (one study, 16 participants). This second study was discontinued early when rofecoxib was withdrawn from the market in 2004. The trials ran from June 2002 to October 2003, and May 2004 to October 2004. We have chosen to include the data from the rofecoxib study as outcomes may be similar when other such NSAIDs are utilised.Partial or complete regression of CIN 2 or 3 occurred in 11 out of 20 (55%) in the treatment arms and five out of 21 (23.8%) in the placebo arms (RR 2.35, 95% CI 1.03 to 5.35; P value 0.04), very low quality evidence). Complete regression of CIN 2 or 3 occurred in four of 12 (33%) of those receiving celecoxib versus two of 13 (15%) of those receiving placebo (RR 2.17, 95% CI 0.48 to 9.76; P value 0.31, very low quality evidence). Partial regression of CIN 2 or 3 occurred in five of 12 (42%) of those receiving celecoxib versus two of 13 (15%) of those receiving placebo (RR 2.71, 95% CI 0.64 to 11.43; P value 0.18), very low quality evidence). Progression to a higher grade of CIN, but not to invasive cancer, occurred in one of 12 (8%) of those receiving celecoxib and two of 13 (15%) receiving placebo (RR 0.54, 95% CI 0.05 to 5.24; P value 0.4, very low quality evidence). One study reported no cases of progression to invasive cancer within the timeframe of the study. No toxicity was reported in either study. Although the studies were well conducted and randomised, some risk of bias was detected in both studies. Furthermore, the duration of the studies was short, which may mask identifying progression to cancer. AUTHORS' CONCLUSIONS: There are currently no convincing data to support a benefit for NSAIDs in the treatment of CIN (very low quality evidence according to GRADE criteria). Results from a large on-going randomised study of celecoxib are awaited.

HPV-associated vulvar carcinoma with sebaceous differentiation.

•Sebaceous carcinoma is rare on the vulva and uncommonly associated with HPV.•Pregnancy may play a role in onset or exacerbation of HPV-associated vulvar cancers.•Treatment of vulvar sebaceous carcinoma is local excision and sentinel lymph node dissection with close follow-up.

Granulosa cell tumor resection with subsequent onset of rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder with an estrogen correlation. The disease can worsen or present with menopause. Granulosa cell tumors (GCT) are estrogen-secreting ovarian sex-cord stromal tumors with median incidence in the early postmenopausal years. We report a 38-year-old female who presented with a 20 cm pelvic mass and elevated inhibin and underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy for a Stage I GCT. She developed progressive post-operative joint pain and weakness before an eventual diagnosis of seropositive RA. With tumor resection and surgical menopause, the patient experienced an abrupt decline in estrogen levels precipitating the onset of RA symptoms. Prior research identified that hormone fluctuation at menopause correlates with onset of RA. While unfortunately direct estrogen measurements were not obtained perioperatively, this case does support circumstantial evidence correlating RA with menopause and a decline in estrogen, irrespective of age.

Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles.

The backbone of ovarian cancer treatment is platinum-based chemotherapy and aggressive surgical debulking. New therapeutic approaches using immunotherapy via immune checkpoint blockade, which have demonstrated clinical efficacy in other tumor types, have been less promising in ovarian cancer. To increase their clinical efficacy, checkpoint inhibitors are now being tested in clinical trials in combination with chemotherapy. Here, we evaluated the impact of cisplatin on tumor immunogenicity and its in vivo roles when used alone or in combination with anti-PD-L1, in two novel murine ovarian cancer cell models. The 2F8 and its platinum-resistant derivative 2F8cis model, display distinct inflammatory profiles and chemotherapy sensitivities, and mirror the primary and recurrent human disease, respectively. Acute and chronic exposure to cisplatin enhances tumor immunogenicity by increasing calreticulin, MHC class I, antigen presentation and T-cell infiltration. Cisplatin also upregulates PD-L1 expression in vitro and in vivo, demonstrating a dual, paradoxical immune modulatory effect and supporting the rationale for combination with immune checkpoint blockade. One of the pathways activated by cisplatin treatment is the cGAS/STING pathway. Chronic cisplatin treatment led to upregulation of cGAS and STING proteins in 2F8cis compared to parental 2F8 cells, while acute exposure to cisplatin further increases cGAS and STING levels in both 2F8 and 2F8cis cells. Overexpression of cGAS/STING modifies tumor immunogenicity by upregulating PD-L1, MHC I and calreticulin in tumor cells. Anti-PD-L1 alone in a platinum-sensitive model or with cisplatin in a platinum-resistant model increases survival. These studies have high translational potential in ovarian cancer.

Immunization of nonautoimmune mice with DNA binding domains of the largest subunit of RNA polymerase I results in production of anti-dsDNA and anti-Sm/RNP antibodies.

Antibodies against the N-terminal (NT) but not the basic domain (BD), DNA binding regions of the largest subunit (S1) of RNA polymerase I (RNAPI) were detected in the sera of MRL-lpr/lpr lupus mice. Antibodies against both RNAPI(S1)-NT and -BD, as well as other systemic lupus erythematosus (SLE) autoantigens (La, ribosomal P proteins and Sm/RNP) were produced by rabbits immunized with anti-DNA antibodies that had been affinity purified from SLE patients. Immunization of nonautoimmune mice (Balb/c) with RNAPI(S1)-NT, RNAPI(S1)-BD, or La in the form of GST fusion proteins, induced production of anti-double-stranded (ds) DNA and anti-Sm/RNP. GST-P1 did not induce an anti-dsDNA response in these mice. These results demonstrate that RNAPI(S1)-NT, RNAPI(S1)-BD and La can participate in an anti-autoantigen/anti-DNA antibody loop during an SLE-like autoimmune response.

Isolated port-site metastasis after robotic hysterectomy for stage IA endometrial adenocarcinoma.

BACKGROUND: Port-site metastasis is a known complication of laparoscopic surgery, although it has been described less in robotic surgery. There are limited reports of such occurrences in current literature. CASES: Two patients underwent robotic-assisted total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection for stage IA endometrial cancer. One patient's surgery was complicated by uterine perforation but the other surgery was uncomplicated. Both patients had development of isolated port-site metastasis and required resection followed by chemotherapy and radiation. CONCLUSION: Port-site metastasis is a surgical complication with an unclear etiology. There are no clear data to suggest a lower incidence with robotic surgery. Patients at low risk for recurrence still may experience development of port-site metastasis.

Short bowel syndrome causing bleeding diathesis and profound vitamin deficiency in pregnancy.

BACKGROUND: Extensive bowel resection may lead to a state of inadequate nutrient absorption and malnutrition known as short bowel syndrome. Deficiencies in fat-soluble vitamins may occur from this condition, with sequelae such as a bleeding diathesis. Maternal vitamin deficiencies also have been associated with fetal anomalies. CASE: A young gravid patient with a history of neonatal bowel resection presented with bleeding diathesis. She subsequently was found to have profound vitamin deficiencies and delivered a newborn with multiple anomalies. CONCLUSION: Preconceptional counseling, nutritional status evaluation, and concomitant management with a gastroenterologist are essential to optimize pregnancy outcome for patients with a history of extensive bowel resection.