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Purpose: The new CAP guideline published in August 2022 recommends using immunohistochemistry (IHC) to test for mismatch repair defects in gastroesophageal (GE), small bowel (SB), or endometrial carcinoma (EC) cancers over next-generation sequencing assessment of microsatellite instability (NGS-MSI) for immune checkpoint inhibitor (ICI) therapy eligibility and states there is a preference to use IHC over NGS-MSI in colorectal carcinoma (CRC)., Methods: We assessed the concordance of NGS-MSI and IHC-MMR from a very large cohort across the spectrum of solid tumors., Results: Of the over 190,000 samples with both NGS-MSI and IHC-MMR about 1,160 were initially flagged as discordant. Of those samples initially flagged as discordant, 50.9% remained discordant after being reviewed by an additional pathologist. This resulted in a final discordance rate of 0.31% (590/191,767). Among CRC, GE, SB and EC, 55.4% of mismatch repair proficient/MSI high (MMRp/MSI-H) tumors had at least one somatic pathogenic mutation in an MMR gene or POLE . Mismatch repair deficient/microsatellite stable (MMRd/MSS) tumors had a significantly lower rate of high tumor mutational burden than MMRp/MSI-H tumors. Across all solid tumors, MMRd/MSI-H tumors had significantly longer overall survival (OS; hazard ratio [HR], 1.47, P < .001) and post-ICI survival (HR, 1.82, P < .001) as compared with MMRp/MSS tumors. The OS for the MMRd/MSS group was slightly worse compared to the MMRp/MSI-H tumors, but this difference was not statistically significant (HR, 0.73, P = .058), with a similar pattern when looking at post-ICI survival (HR, 0.43, P = .155)., Conclusion: This study demonstrates that NGS-MSI is noninferior to IHC-MMR and can identify MSI-H tumors that IHC-MMR is unable to detect and conversely IHC-MMR can identify MMRd tumors that NGS-MSI misses.

Purpose: Evaluation by a gynecologic oncologist (GO) is associated with improved clinical outcomes for patients with gynecologic cancers, yet little is known about health care factors that influence patients' referrals to GO., Methods: Medical records of 50 consecutive new patients seen in GO clinics at each of six referral centers across the United States were reviewed. Patient and disease characteristics were collected along with referral indication, evaluation and referral dates, diagnostic procedures, provider specialties, and zone improvement plan (ZIP) code of up to three referring providers per patient. The primary outcome was interval between first evaluation and referral. Univariate associations were evaluated with Chi-square and Wilcoxon rank-sum tests and multivariable associations with negative binomial regression models. Secondary outcome was prolonged time to GO referral, defined as greater than the 75th percentile. Logistic regression was used for multivariable modeling., Results: Three hundred patient records were analyzed. The median time from first health care encounter to referral was 15 days (IQR, 5-43). The mean distance from residence to GO was 39.8 miles (standard deviation, 53.8). Seventy-one percent of GO referrals were initiated by obstetrician-gynecologists, 9% by family physicians, and 6% internists. Presentation-to-referral interval was 76% shorter for patients evaluated by an emergency medicine clinician (exp(Beta), 0.24; 95% CI, 0.11 to 0.53; P < .001). Public insurance was associated with 1.47 times longer time to referral compared with private insurance (exp(Beta), 1.47; 95% CI, 1.05 to 2.04; P = .001). Residents of nonmetropolitan ZIP codes were less likely to have prolonged time to referral (odds ratio [OR], 0.288; P = .017). Distance from residence to GO (per 10 miles) increased the likelihood of prolonged time to referral (OR, 1.10; P = .010)., Conclusion: Interventions are needed to improve recognition and referral of patients for gynecologic oncology evaluation. Community outreach and engagement with obstetrician-gynecologists should be prioritized to improve times to referral.

Objective: The treatment for high risk or recurrent gestational trophoblastic neoplasia (GTN) is a highly toxic multi-agent chemotherapy. For patients with progressive or recurrent GTN, checkpoint inhibitors have demonstrated anti-tumor activity; however, identification of novel therapies for GTN remain an unmet need. Therefore, we sought to characterize the molecular landscape of GTN to identify potential therapeutic targets., Methods: GTN samples were analyzed using a combination of molecular - next-generation sequencing (NGS) or whole exome sequencing (WES)- and protein- Immunohistochemistry (IHC) analyses. GTN samples encompassed complete moles, choriocarcinoma, epithelioid trophoblastic tumors (ETT), and placental site trophoblastic tumors (PSTT)., Results: We analyzed 30 cases of GTN including 15 choriocarcinoma, 7 ETT, 5 PSTT, 1 invasive mole and 2 mixed histologies. The median age was 41.5. GTN samples were found to be PD-L1 positive (92.3%), tumor mutational burden (TMB) low (92.8%), and microsatellite stable (MSS) (100%). Forty-six percent of choriocarcinoma specimens contained a genomic alteration including TP53 (33%) and homologous recombination repair (HRR) (13%) genes. Alterations in RTK-RAS pathway signaling was present in 40% of ETT cases., Conclusions: The high rate of PD-L1 positivity in this real-world database and reported in prior literature support continued clinical trial development evaluating immunotherapy for treatment of GTN. Other potential targeted treatments identified include Wee1, PARP and MEK inhibitors based on molecular alterations in TP53, HRR genes, and RTK-RAS pathways respectively., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Leah McNally: None. Sharon Wu: employee of Caris Life Sciences. Kurt Hodges: employee of Caris Life Sciences. Matt Oberley: employee of Caris Life Sciences. John J Wallbillich: None. Nathaniel L Jones: None. Thomas J Herzog: Scientific Advisory Boards &/or Honorarium: Aadi Bioscience, Astra Zeneca, Caris, Clovis, Eisai, Epsilogen, Genentech, GSK, J&J, Merck, Mersana, Novocure, Seattle Genetics. Premal H Thaker: Grants to institution from: Merck and GSK. Scientific Advisory Boards: AstraZeneca, GlaxoSmithKline, Immunon, Immunogen, SeaGen, Novocure, Mersana, Verastem, Zentalis. Angeles Alvarez Secord: Duke receives Clinical trial grant funding from AbbVie, Aravive, AstraZeneca, Clovis, Eisai, Ellipses Pharma, GSK, I-MAB Biopharma, Immunogen, Merck, Oncoquest, Roche/Genentech, Seagen, Inc., Theradex, VBL, Zentalis, and the National Cancer Trial Network. Advisory Boards (uncompensated) for AstraZeneca, Clovis, Gilead, GSK, Immunogen, Imvax, Merck, Mersana, Natera, Onconova, Oncoquest. Participation on Steering Committees (uncompensated): Aravive (AxXelerate); Roche/Genentech (AtTEND trial); VBL (OVAL trial); and Oncoquest (GOG-3035/FLORA-5). SGO Board of Directors, GOG Foundation Board of Directors, AAOGF Board of Trustees. Marilyn Huang: University of Miami received clinical grant funding fromMerck, Jansen; Scientific advisory board: Clovis, Seattle Genetics, Eisai, Immunogen, VB111, Tesaro/GSK, Voluntis/Aptar Digital Health., (Published by Elsevier Inc.)

Vulvar squamous cell cancer (VSC) accounts for 90% of vulvar cancers. Next-generation sequencing studies of VSC imply human papillomavirus (HPV) and p53 status play separate roles in carcinogenesis and prognosis. We sought to describe the genomic landscape and analyze the immunologic profiles of VSC with respect to HPV and p53 status. A total of 443 VSC tumors underwent tumor profiling. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor samples. PD-L1, microsatellite instability were tested by fragment analysis, IHC, and next-generation sequencing. Tumor mutational burden-high was defined as >10 mutations per MB. HPV 16/18 positive (HPV+) status was determined using whole exome sequencing on 105 samples. Three cohorts were identified from 105 samples with known HPV: HPV+, HPV-/p53wt, and HPV-/p53mt. Where HPV and p53 status were examined, TP53 mutations were exclusive of HPV+ tumors. In all, 37% of samples were HPV+. Among the 66 HPV- tumors, 52 (78.8%) were HPV-/p53mt and 14 (21.2%) were HPV-/p53wt. The HPV-/p53wt cohort had a higher rate of mutations in the PI3KCA gene (42.9% HPV-/p53wt vs 26.3% HPV+ vs. 5.8% HPV-/p53mt, q =0.028) and alterations in the PI3K/AkT/mTOR pathway (57.1% HPV-/p53wt vs. 34.2% HPV+ vs. 7.7% HPV-/p53mt, q =0.0386) than the other 2 cohorts. Ninety-eight VSC tumors with HPV16/18 information underwent transcriptomic analysis and immune deconvolution method. No differences were observed in immune profiles. The HPV-/p53wt VSC tumors had significantly higher rates of mutations in the PI3KCA gene and alterations in the PI3K/AkT/mTOR pathway, a potential target that merits further investigation in this subgroup., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with overall incidence increasing, particularly high-grade disease. There is sparse information regarding quality of life (QOL) in EC survivors with a focus on grade of disease., Methods: A total of 259 women with EC diagnosed between 2016 and 2020 were identified via the Metropolitan Detroit Cancer Surveillance System and consented to enroll in the Detroit Research on Cancer Survivors cohort study (if African American, n = 138) or completed the baseline interview (if non-Hispanic white, n = 121). Each respondent provided information about their health history, educational attainment, health behaviors, and demographics. The Functional Assessment of Cancer Therapy-General (FACT-G) and Endometrial-specific (FACT-En) were used to assess QOL., Results: Women diagnosed with high-grade (n = 112) and low-grade (n = 147) EC participated in this study. EC survivors with high-grade disease reported significantly lower QOL compared to survivors with low-grade disease (85 vs. 91, respectively, p value = 0.025) as assessed by the FACT-G. This difference was driven by lower physical and functional subscales among women with high-grade disease compared to those with low-grade disease (p value = 0.016 and p = 0.028, respectively). Interestingly, EC-specific QOL measures, as assessed by the FACT-En, did not differ by grade., Conclusion: Grade of disease impacts QOL in EC survivors, as well as socioeconomic, psychological, and physical factors. Most of these factors are amenable to interventions and should be assessed in patients after an EC diagnosis., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To compare the frequencies of somatic homologous recombination (HR) gene mutations identified in next-generation sequencing (NGS) genomic profiling of uterine serous carcinomas (USCs) and high-grade serous ovarian carcinomas (HGSOCs)., Methods: Data for this analysis was obtained from AACR Project GENIE, a multi-institutional dataset of clinical-grade NGS genomic profiling results for many cancer sites and histologic subtypes, through cBioPortal. Patient/specimen groups used for analysis were USC and HGSOC. 14 HR genes were queried for each group with respect to mutation frequency. For each HR gene, the difference in mutation frequency between the two groups was evaluated using Fisher's exact test. The threshold for statistical significance was p-value < .05., Results: In the USC group, there were 457 samples from 451 patients. In the HGSOC group, there were 1537 samples from 1515 patients. The most frequently mutated HR gene for USC was BRCA2 (4.84%) and for HGSOC was BRCA1 (9.07%). Mutation frequency was significantly different between USC and HGSOC for BRCA 1 (p < .001) and BRCA2 (p = .0379). For the 12 non-BRCA HR genes, mutation frequency was not significantly different between USC and HGSOC. The rate of patients with at least one HR gene mutation in their profiled tumor was 16.85% for USC and 25.21% of HGSOC. Most USC patients with a somatic HR mutation had only one HR gene mutated., Conclusions: Somatic HR gene mutations were commonly identified in NGS genomic profiling of USC. Mutation frequencies for non-BRCA HR genes were not significantly different between USC and HGSOC. These data add to the growing rationale for HR deficiency tumor testing and targeting (e.g., with PARP inhibitors) in future clinical trial development for women with USC., Competing Interests: Declaration of Competing Interest Dr. Wallbillich and Dr. Ali-Fehmi have nothing to disclose. Dr. Morris reports personal fees from AstraZeneca, personal fees from Clovis, personal fees from GSK, outside the submitted work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Survival for patients with newly diagnosed cervical cancer has not significantly improved over the past several decades. We sought to identify a clinically relevant set of prognostic genes for squamous cell carcinoma of the cervix (SCCC), the most common cervical cancer subtype. Using RNA-sequencing data and survival data from 203 patients in The Cancer Genome Atlas (TCGA), we conducted a series of analyses using different decile cutoffs for gene expression to identify genes that could indicate large and consistent survival differences across different decile cutoffs of gene expression. Those analyses identified 42 high-risk genes. A patient's survivability could be estimated by simply counting the number of high-risk genes with extremely high expression (above the 90 th percentile) or estimating a transcriptomic risk score (TRS) using a machine learning algorithm with 9 of the 42 genes. On multivariate analysis, the significant predictors of mortality included high TRS (HR = 44.8), stage IV (HR = 28.1), intermediate TRS (HR = 4.75), and positive lymph node status (HR = 2.92). Approximately 18% of earlier-stage patients were identified as a poor-prognosis subgroup with high TRS. In patients with SCCC, transcriptomic risk appears to better predict survival than clinical prognostic factors, including stage., Competing Interests: None., (AJCR Copyright © 2020.)

Objectives: To develop a transcriptomic signature capable of predicting overall survival (OS) for uterine serous carcinoma (USC)., Methods: RNAseq data for 58 USC patients were obtained from TCGA. Expression of 73 candidate genes was measured for 67 Augusta University (AU) samples using NanoString technology., Results: Analysis of the TCGA RNAseq data identified 73 genes that individually predict prognosis for USC patients and an elastic net model with all 73 genes (USC73) distinguishes a good OS group with low USC73 score from a poor OS group with high USC73 score (5-year OS = 83.3% and 13.3% respectively, HR = 40.1; p = 3 × 10 -8 ). This finding was validated in the independent AU cohort (HR = 4.3; p = 0.0004). The poor prognosis group with high USC73 score consists of 37.9% and 32.8% of patients in the TCGA and AU cohort respectively. USC73 score and pathologic stage independently contribute to OS and together provide the best prognostic value. Early stage, low USC73 patients have the best prognosis (5-year OS = 85.1% in the combined dataset), while advanced stage, high USC73 patients have the worst prognosis (5-year OS = 6.4%, HR = 30.5, p = 1.2 × 10 -12 ). Consistent with the observed poor survival, primary cell cultures from high USC73 patients had higher proliferation rate and cell cycle progression; and high USC73 patients had lower rates of complete response to standard therapy., Conclusions: The USC73 transcriptomic signature and stage independently predict OS of USC patients and the best prediction is achieved using USC73 and stage. USC73 may also serve as a therapeutic biomarker to guide patient care., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Uveal melanoma (UM) is a major intraocular cancer that is molecularly distinct from cutaneous melanoma. Approximately half of patients with UM eventually develop metastasis. The prognosis of metastatic UM is poor, with a median overall survival (OS) of less than a year. In this study, we sought to identify microRNAs (miRNAs) associated with metastasis and OS in UM. We analyzed the miRNA expression and clinical outcomes data from The Cancer Genome Atlas (TCGA) dataset for UM. Differential expression analyses were conducted for each miRNA with respect ever-development of metastasis. Multiple survival analyses were done, using the Cox proportional hazards model, to evaluate interactions between miRNA expression, metastasis, and OS. A total of 22 miRNAs (3 upregulated and 19 downregulated) were differentially expressed between patients with vs. without metastatic UM. These 22 miRNAs could be grouped into four clusters based on similarities in expression patterns. Of the 22 miRNAs differentially expressed with respect to metastasis, 21 were significantly associated with OS. The expression of multiple miRNAs was significantly associated with metastasis and overall survival in patients with UM. Further investigation of these miRNAs as biomarkers and/or therapeutic targets is warranted in the push to improve outcomes for patients with metastatic UM., Competing Interests: CONFLICTS OF INTEREST The authors declare no relevant conflicts of interest.

Objective: To measure anti-glycan antibodies (AGA) in cervical cancer (CC) patient sera and assess their effect on therapeutic outcome., Patients and Methods: Serum AGA was measured in 276 stage II and 292 stage III Peruvian CC patients using a high content and throughput Luminex multiplex glycan array (LMGA) containing 177 glycans. Association with disease-specific survival (DSS) and progression free survival (PFS) were analyzed using Cox regression., Results: AGAs were detected against 50 (28.3%) of the 177 glycans assayed. Of the 568 patients, 84.5% received external beam radiation therapy (EBRT) plus brachytherapy (BT), while 15.5% only received EBRT. For stage-matched patients (Stage III), receiving EBRT alone was significantly associated with worse survival (HR 6.4, p < 0.001). Stage III patients have significantly worse survival than Stage II patients after matching for treatment (HR = 2.8 in EBRT+BT treatment group). Furthermore, better PFS and DSS were observed in patients positive for AGA against multiple glycans belonging to the blood group H, Lewis, Ganglio, Isoglobo, lacto and sialylated tetrarose antigens (best HR = 0.49, best p = 0.0008)., Conclusions: Better PFS and DSS are observed in cervical cancer patients that are positive for specific antiglycan antibodies and received brachytherapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Hypoxia-mediated tumor progression, metastasis, and drug resistance are major clinical challenges in ovarian cancer. Exosomes released in the hypoxic tumor microenvironment may contribute to these challenges by transferring signaling proteins between cancer cells and normal cells. We observed that ovarian cancer cells exposed to hypoxia significantly increased their exosome release by upregulating Rab27a, downregulating Rab7, LAMP1/2, NEU-1, and also by promoting a more secretory lysosomal phenotype. STAT3 knockdown in ovarian cancer cells reduced exosome release by altering the Rab family proteins Rab7 and Rab27a under hypoxic conditions. We also found that exosomes from patient-derived ascites ovarian cancer cell lines cultured under hypoxic conditions carried more potent oncogenic proteins-STAT3 and FAS that are capable of significantly increasing cell migration/invasion and chemo-resistance in vitro and tumor progression/metastasis in vivo. Hypoxic ovarian cancer cells derived exosomes (HEx) are proficient in re-programming the immortalized fallopian tube secretory epithelial cells (FT) to become pro-tumorigenic in mouse fallopian tubes. In addition, cisplatin efflux via exosomes was significantly increased in ovarian cancer cells under hypoxic conditions. Co-culture of HEx with tumor cells led to significantly decreased dsDNA damage and increased cell survival in response to cisplatin treatment. Blocking exosome release by known inhibitor Amiloride or STAT3 inhibitor and treating with cisplatin resulted in a significant increase in apoptosis, decreased colony formation, and proliferation. Our results demonstrate that HEx are more potent in augmenting metastasis/chemotherapy resistance in ovarian cancer and may serve as a novel mechanism for tumor metastasis, chemo-resistance, and a point of intervention for improving clinical outcomes.

The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 ( pSTAT3 Tyr705 ) and suppression or loss of protein inhibitor of activated STAT3 ( PIAS3 ) in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal-peritoneal junction (TPJ), p53 signature FT tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of STAT3/PIAS3 (compared with their known TP53 signature) and their target proliferation genes. We observed constitutive activation of STAT3 and low levels or loss of PIAS3 in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of pSTAT3 Tyr705 and decreased levels of PIAS3 appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared with high PIAS3 and low pSTAT3 expression in normal benign FT). Exogenous expression of STAT3 in FT cells mediated translocation of pSTAT3 and c-Myc into the nucleus. In vivo experiments demonstrated that overexpression of STAT3 in FT secretory epithelial cells promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus, we conclude that the STAT3 pathway plays a role in the development and progression of HGSC from its earliest premalignant states. Significance: Concomitant gain of pSTAT3 Tyr705 and loss of PIAS3 appear critical for initiation and development of high-grade serous carcinoma. Cancer Res; 78(7); 1739-50. ©2018 AACR ., (©2018 American Association for Cancer Research.)

A 20 year old with recurrent low-grade serous carcinoma (LGSC) is discussed. The differential diagnosis, pathology, epidemiology, treatment options are discussed. Focus on the molecular pathways of LGSC and the implications of the diagnosis on fertility are highlighted., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: STAT3 is over-expressed in endometrial cancer, and diabetes is a risk factor for the development of type 1 endometrial cancer. We therefore investigated whether glucose concentrations influence STAT3 expression in type 1 endometrial cancer, and whether such STAT3 expression might be inhibited by metformin., Methods: In Ishikawa (grade 1) endometrial cancer cells subjected to media with low, normal, or high concentrations of glucose, expression of STAT3 and its target proteins was evaluated by real-time quantitative PCR (qPCR). Ishikawa cells were treated with metformin and assessed with cell proliferation, survival, migration, and ubiquitin assays, as well as Western blot and qPCR. Expression of apoptosis proteins was evaluated with Western blot in Ishikawa cells transfected with a STAT3 overexpression plasmid and treated with metformin. A xenograft tumor model was used for studying the in vivo efficacy of metformin., Results: Expression of STAT3 and its target proteins was increased in Ishikawa cells cultured in high glucose media. In vitro, metformin inhibited cell proliferation, survival and migration but induced apoptosis. Metformin reduced expression levels of pSTAT3 ser727, total STAT3, and its associated cell survival and anti-apoptotic proteins. Additionally, metformin treatment was associated with increased degradation of pSTAT3 ser727. No change in apoptotic protein expression was noticed with STAT3 overexpression in Ishikawa cells. In vivo, metformin treatment led to a decrease in tumor weight as well as reductions of STAT3, pSTAT3 ser727, its target proteins., Conclusions: These results suggest that STAT3 expression in type 1 endometrial cancer is stimulated by a high glucose environment and inhibited by metformin., Competing Interests: The authors have declared that no competing interests exist.

Although activation of the STAT3 pathway has been associated with tumor progression in a wide variety of cancer types (including ovarian cancer), the precise mechanism of invasion and metastasis due to STAT3 are not fully delineated in ovarian cancer. We found that pSTAT3 Tyr705 is constitutively activated in patient ascites and ascites-derived ovarian cancer cells (ADOCCs), and the range of STAT3 expression could be very high to low. In vivo transplantation of ADOCCs with high pSTAT3 expression into the ovarian bursa of mice resulted in a large primary tumor and widespread peritoneal metastases. In contrast, ADOCCs with low STAT3 expression or ADOCCs with STAT3 expression knockdown, led to reduced tumor growth and an absence of metastases in vivo. Cytokines derived from the ADOCC culture medium activate the interleukin (IL)-6/STAT pathway in the STAT3 knockout (KO) cells, compensating for the absence of inherent STAT3 in the cells. Treatment with HO-3867 (a novel STAT3 inhibitor at 100 p.p.m. in an orthotopic murine model) significantly suppressed ovarian tumor growth, angiogenesis and metastasis by targeting STAT3 and its downstream proteins. HO-3867 was found to have cytotoxic effects in ex vivo cultures of freshly collected human ovarian cancers, including those resistant to platinum-based chemotherapy. Our results show that STAT3 is necessary for ovarian tumor progression/metastasis and highlight the potential for targeting STAT3 by HO-3867 as a therapeutic strategy for ovarian cancer.

Objective: To assess the cost-effectiveness of a strategy employing genomic-based tumor testing to guide therapy for platinum-resistant ovarian cancer., Methods: A decision model was created to compare standard of care (SOC) cytotoxic chemotherapy to a genomic-based treatment strategy. The genomic arm included tumor testing with treatment directed at targets identified. Overall survival was assumed to be similar between strategies; quality of life (QOL) was assumed superior during targeted therapy compared to chemotherapy. Pertinent uncertainties (cost of targeted therapy and genomic testing, response to targeted therapy, probability of a tumor having a targetable alteration, and impact on QOL) were evaluated in a series of one-and two-way sensitivity analyses., Results: The genomic testing strategy was more expensive ($90,271 vs. $74,926) per patient than SOC. The incremental cost-effectiveness ratio (ICER) of the genomic strategy was $479,303 per quality-adjusted life year saved (QALY). Model results were insensitive to the cost of genomic testing, differences in QOL, and the probability of identifying a targetable alteration. However, the model was sensitive to the cost of targeted therapy. For example, when the cost of targeted therapy was reduced to 56% of its current cost (or $6400/cycle), the genomic strategy became more cost-effective with an ICER of $96,612/QALY., Conclusions: Genomic-based tumor testing and targeted therapy in patients with platinum-resistant ovarian cancer is not cost-effective compared with SOC. However, reducing the cost of targeted therapy (independently, or in combination with reducing the cost of the genomic test) provides opportunities for improved value in cancer care., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Exosomes are nano-sized (20-100nm) vesicles released by a variety of cells and are generated within the endosomal system or at the plasma membrane. There is emerging evidence that exosomes play a key role in intercellular communication in ovarian and other cancers. The protein and microRNA content of exosomes has been implicated in various intracellular processes that mediate oncogenesis, tumor spread, and drug resistance. Exosomes may prime distant tissue sites for reception of future metastases and their release can be mediated by the tumor microenvironment (e.g., hypoxia). Ovarian cancer-derived exosomes have unique features that could be leveraged for use as biomarkers to facilitate improved detection and treatment of the disease. Further, exosomes have the potential to serve as targets and/or drug delivery vehicles in the treatment of ovarian cancer. In this review we discuss the biological and clinical significance of exosomes relevant to the progression, detection, and treatment of ovarian cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Cervical adenocarcinoma in situ (AIS) is increasing in incidence among reproductive-age women. Cervical conization is an alternative to hysterectomy that allows future fertility, however reports regarding the risk of residual AIS and underlying adenocarcinoma are conflicting. The purpose of this study was to determine the outcomes of a large cohort of women treated for AIS., Methods: The medical records of 180 women with cervical AIS evaluated at the University of Texas MD Anderson Cancer Center and its outlying clinics between 1983 and 2011 were reviewed for demographic information, treatment history, pathologic findings and outcomes., Results: The mean age at diagnosis was 33.8years (range 17.6-76.1years). 172 of the 180 women had at least one cone biopsy performed, with 110 (64.0%) undergoing a cold knife cone (CKC), and 62 (36.0%) undergoing a loop electrosurgical excision procedure (LEEP) as their initial method of treatment. Positive margins were noted in 35.0% of patients undergoing CKC compared with 55.6% undergoing LEEP (p=0.017). 71 patients ultimately underwent hysterectomy with residual disease noted in 10 patients (14.1%), 8 patients (11.3%) with residual AIS and 2 patients (2.8%) with invasive carcinoma. Of the 101 patients who did not undergo hysterectomy, 2 patients (2.0%) developed recurrent AIS at a median of 27.5months (range 18-37months) from the last cone, and none developed invasive carcinoma., Conclusion: Patients undergoing conservative management for AIS with cervical conization alone should be monitored closely and counseled regarding the potential risks of residual and recurrent disease, even when negative cone margins are obtained., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To evaluate demographic and clinical characteristics associated with the development of vulvar intraepithelial neoplasia (VIN 2/3), and factors associated with recurrence., Methods: A retrospective chart review of 303 patients with VIN 2/3 evaluated at a single institution between 1993 and 2011 was performed. Medical records were reviewed for demographic information, risk factors, treatment type, pathologic diagnosis, and recurrence/outcome information., Results: Median age at diagnosis was 47 years (range 14-87). 40% of patients reported current tobacco use and 26% reported previous use. Primary treatment included excision (n=176, 59%), laser ablation (n=40, 13%), imiquimod (n=22, 7.4%), excision with laser (n=24, 8.1%), excision with imiquimod (n=10, 3.4%), and laser with imiquimod (n=3, 1.0%). 92 patients (62.6%) were noted to have positive margins, which was associated with larger tumor size (p=0.004). 87 patients (28.7%) developed recurrent disease, which was associated with smoking (p<0.001), larger lesion size (p=0.016), and positive margins (p=0.005). On univariate analysis, higher rates of recurrence were associated with laser ablation (45.0%) compared with excision (26%) or imiquimod (13.6%) (p=0.018). However, on multivariate analysis of recurrence-free survival (RFS) these therapies were equivalent when used individually, but the use of excision plus laser had an adverse impact on RFS (p<0.001). 7 patients (2.3%) recurred with invasive disease a median of 109 months (range 12-327) from initial VIN 2/3 diagnosis., Conclusions: This large cohort of women with VIN 2/3 further delineates the demographic and clinical factors associated with VIN 2/3. High rates of recurrence were noted and found to be associated with smoking, larger lesion size, and positive margins. While higher rates of recurrence were found among those treated with laser ablation, it was not inferior with respect to RFS when used alone, but the use of laser with excision was associated with decreased RFS. Our findings provide hypothesis-generating material for further research in the management of VIN2/3., (Copyright © 2012 Elsevier Inc. All rights reserved.)

► Ovarian small-cell carcinoma of the hypercalcemic type is a rare neoplasm with no standard treatment. ► The chemotherapy regimen including vinblastine, cisplatin, cyclophosphamide, bleomycin, doxorubicin and etoposide (VPCBAE) has limited toxicities and was effective in the 3 patients described in this case report.