Presence of 10 transformation zone cells in endocervical curettage should not be required for adequacy.

OBJECTIVES: In another publication, we concluded endocervical curettage (ECC) should have a minimum number of squamous cells for adequacy, similar to the requirements for adequate cervical Papanicolaou smears. Here, we investigate if also, similar to cervical Papanicolaou smears, the presence of at least 10 cells from the endocervical/transformation zone (EC/TZ) in ECCs should be used as a quality assurance measure or if, instead, at least 10 EC/TZ cells should be part of the adequacy criteria for ECC, with an emphasis on diagnosis of at least high-grade squamous dysplasia (HGD). METHODS: All patients with at least HGD diagnosed on an excisional biopsy specimen (loop electrosurgical excision procedure [LEEP]) from May 1, 2018, to December 31, 2019, and an ECC in the preceding 6 months at our institution were included. Number of EC/TZ cells present in ECCs was counted visually and categorized as less than or greater than 10 TZ cells. A χ2 test was used to evaluate the proportion of ECCs with and without HGD and the presence or absence of at least 10 EC/TZ cells. Given our recent work encouraging at least 1000 squamous cells in an ECC to be considered adequate, we also evaluated only ECCs with greater than 1000 squamous cells with and without HGD and the presence or absence of at least 10 EC/TZ cells. P value was <.05. RESULTS: Fifty-one LEEPs with HGD and a preceding ECC in the previous 6 months were identified. Of the 51 ECCs, 6 had fewer than 10 EC/TZ cells and 45 had at least 10 EC/TZ cells. A similar proportion of the ECCs with HGD had at least 10 EC/TZ cells as those without HGD (93% vs 86%, P = .53). Using only ECCs with greater than 1000 squamous cells, we still found no statistical difference in the proportion of ECCs with HGD having greater than 10 EC/TZ cells compared to those without HGD (91% vs 100%, P = .49). CONCLUSIONS: We found that the presence of at least 10 EC/TZ cells does not increase the likelihood of finding HGD in an ECC performed in the 6 months prior to a LEEP with HGD. Similar to the use of the TZ component in cervical Papanicolaou smears, the presence or absence of at least 10 TZ cells in an ECC should only be considered a quality assurance measure and not be used as a criterion for adequacy of the specimen.

Adequacy in Endocervical Curettage.

OBJECTIVES: Specimen adequacy is an important quality assurance component of a cervical Papanicolaou test. Although consensus exists on minimal acceptable cellularity for cervical Papanicolaou tests, no such criteria exist for endocervical curettage (ECC) specimens. We sought to identify minimum acceptable cellularity for accurate diagnosis of high-grade dysplasia (HGD) on ECC. METHODS: All patients with HGD diagnosed in a loop electrosurgical excision procedure (LEEP) from May 8, 2018, to December 18, 2019, and an ECC in the preceding 6 months at our institution were included (n = 51). All ECCs performed before the LEEP were evaluated for cellularity of squamous cells using Aperio eSlide Manager (Leica Biosystems). Biopsy results concurrent with the ECC were noted. We compared the number of squamous cells in positive and negative ECC specimens using a t-test. The proportion of ECC specimens and concurrent biopsies undergoing immunohistochemical (IHC) staining for p16 were compared using the χ2 test. P < .05 was considered significant. RESULTS: Endocervical curettage specimens positive for HGD have increased cellularity compared with negative ECC specimens (mean cellularity, 10,165 vs 1,055; P < .05). Further, IHC staining for p16 was more likely to be performed on an ECC specimen positive for HGD than on a negative ECC specimen (50% vs 3%; P < .05). Biopsies performed concurrently with a negative ECC finding were more likely to undergo p16 IHC than biopsies performed concurrently with a positive ECC finding (51% vs 7%; P < .05). Finally, we observed no difference in the proportion of biopsies undergoing IHC staining for p16 when comparing biopsies positive for HGD with negative biopsies (37% vs 46%; P = .33). CONCLUSIONS: We find cellularity of approximately 10,000 cells adequate to diagnose HGD in an ECC specimen and cellularity of approximately 1,000 cells to be inadequate. Further, we find p16 IHC commonly used as a "rule-in" test on ECC specimens at our institution. Biopsies accompanying an ECC specimen negative for HGD are more likely to undergo p16 IHC than those accompanying an ECC specimen positive for HGD, but there is no difference in the proportion of biopsies undergoing p16 IHC when comparing positive and negative results in the biopsies themselves. These findings further support the need for adequate cellularity for diagnosis in ECC, especially when a biopsy is technically difficult. Further areas for exploration include investigating laboratory procedures to maximize the cellularity of ECC specimens.

COVID-19 Infection During Pregnancy Induces Differential Gene Expression in Human Cord Blood Cells From Term Neonates.

Background: The COVID-19 pandemic continues worldwide with fluctuating case numbers in the United States. This pandemic has affected every segment of the population with more recent hospitalizations in the pediatric population. Vertical transmission of COVID-19 is uncommon, but reports show that there are thrombotic, vascular, and inflammatory changes in the placenta to which neonates are prenatally exposed. Individuals exposed in utero to influenza during the 1918 pandemic had increased risk for heart disease, kidney disease, diabetes, stomach disease and hypertension. Early exposure of COVID-19 during fetal life may lead to altered gene expression with potential long-term consequences. Objective: To determine if gene expression is altered in cord blood cells from term neonates who were exposed to COVID-19 during pregnancy and to identify potential gene pathways impacted by maternal COVID-19. Methods: Cord blood was collected from 16 term neonates (8 exposed to COVID-19 during pregnancy and 8 controls without exposure to COVID-19). Genome-wide gene expression screening was performed using Human Clariom S gene chips on total RNA extracted from cord blood cells. Results: We identified 510 differentially expressed genes (374 genes up-regulated, 136 genes down-regulated, fold change ≥1.5, p-value ≤ 0.05) in cord blood cells associated with exposure to COVID-19 during pregnancy. Ingenuity Pathway Analysis identified important canonical pathways associated with diseases such as cardiovascular disease, hematological disease, embryonic cancer and cellular development. Tox functions related to cardiotoxicity, hepatotoxicity and nephrotoxicity were also altered after exposure to COVID-19 during pregnancy. Conclusions: Exposure to COVID-19 during pregnancy induces differential gene expression in cord blood cells. The differentially expressed genes may potentially contribute to cardiac, hepatic, renal and immunological disorders in offspring exposed to COVID-19 during pregnancy. These findings lead to a further understanding of the effects of COVID-19 exposure at an early stage of life and its potential long-term consequences as well as therapeutic targets.

Rare occurrence of pseudomyxoma peritonei (PMP) syndrome arising from a malignant transformed ovarian primary mature cystic teratoma treated by cytoreductive surgery and HIPEC: a case report.

BACKGROUND: Pseudomyxoma peritonei (PMP) syndrome is a disease process that typically occurs from ruptured appendiceal mucocele neoplasms. PMP syndrome arising from malignant transformation of an ovarian primary mature cystic teratoma (MCT) is a pathogenesis rarely encountered. CASE PRESENTATION: Herein, we report a 28-year-old patient evaluated and treated for a right ovarian mass and large volume symptomatic abdominopelvic mucinous ascites. Molecular profiling and genetic analysis revealed mutations in ATM, GNAS, and KRAS proteins while IHC demonstrated gastrointestinal-specific staining for CK20, CDX2, CK7, and SATB2. Peritoneal cytology showed paucicellular mucin. Diffuse peritoneal adenomucinosis (DPAM) variant of PMP arising from a ruptured ovarian primary MCT after malignant transformation to a low-grade appendiceal-like mucinous neoplasm was ultimately confirmed. Treatment included staged therapeutic tumor debulking and right salpingo-oophorectomy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). CONCLUSIONS: Our report builds upon the existing literature supporting this aggressive treatment option reserved for advanced abdominal malignancies utilized in this patient with a rare clinical entity.

Clinical Characteristics and Histologic Features of Hysterectomy Specimens From Transmasculine Individuals.

OBJECTIVE: To describe the clinical characteristics of transmasculine individuals who underwent hysterectomy and characterize surgical pathology findings. METHODS: Under an institutional review board-approved protocol, transmasculine individuals who were undergoing hysterectomy and bilateral salpingectomy or bilateral salpingo-oophorectomy were retrospectively identified from a single institution. Past medical, surgical, obstetric, and gynecologic history were collected, including prior testosterone use, cervical cancer screening status, and preoperative pelvic imaging. Surgical pathologic findings of the endometrium, ovaries, and cervix were collected. RESULTS: A total of 72 individuals were included. The median age was 30 years (range 19-51). The majority of patients had private insurance (n=53, 74%) and were on testosterone at time of the preoperative visit (n=63, 88%). Forty-two patients (58%) reported anxiety, depression, or bipolar disorder, and 34 patients (47%) were taking an antidepressant or mood stabilizer. Of the 68 patients eligible for cervical cancer screening, 33 (49%) were up to date before their surgical consultation visits. Pelvic pain was the leading indication for surgery (n=65, 90%), and 29 patients (40%) had multiple listed indications for surgery. Surgical pathology results included cervical intraepithelial neoplasia 2-3 in three patients (4%), endometrial or cervical atrophy in 13 patients (18%), and ovarian or paratubal cysts in 16 patients (22%). CONCLUSION: This study describes the distinct clinical characteristics and surgical pathology findings that health care professionals should consider when caring for this unique patient population, including a relatively high rate of mental health conditions, pelvic pain as the leading indication for surgery, and the presence of endometrial or cervical atrophy and ovarian or paratubal cysts on surgical pathology.

Digital Quantification of Ki-67 and PHH3 in the Classification of Uterine Smooth Muscle Tumors.

Uterine smooth muscle tumors are the most common tumors of the female genital tract and include leiomyoma (LM) and its variants, smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcoma (LMS). Accurate diagnosis of LMS is determined by nuclear atypia, mitotic count, and the presence or absence of tumor cell necrosis, a process which is often difficult and subjective. In this study, we correlated digital quantification of proliferation marker Ki-67 and mitotic marker phosphohistone H3 (PHH3) to mitotic count, classification of uterine smooth muscle tumors, and clinical outcomes. A total of 39 cases (17 LMS, 5 STUMP, 10 LM with bizarre nuclei, and 7 LM) were included. Mitotic count, Ki-67, and PHH3 were significantly correlated. When comparing the LMS group to the STUMP, LM with bizarre nuclei, and LM groups combined, LMS showed a significantly greater digital quantification of Ki-67 (median 10.6% vs. 0.4%, P<0.001) and PHH3 (median 0.5% vs. 0.14%, P=0.022). Ki-67 was a better predictor of LMS compared with PHH3 (area under the curve 0.92 vs. 0.73, P=0.017). Above a threshold Ki-67 value of 3.8%, the sensitivity was 82% and specificity was 91%. Clinical outcomes were available for 10 patients (8 LMS and 2 STUMP), and inferior progression-free survival was noted for patients with higher Ki-67 values. Overall, this study suggests that digital quantification of Ki-67 can potentially aid in diagnosis of LMS.

The compliance with a patient-safety bundle for management of placenta accreta spectrum†.

OBJECTIVE: Our objective was to evaluate the compliance with a patient-safety bundle for placenta accreta spectrum (PAS) by comparing the implementation of the components of the patient-safety bundle in the pre- and post-protocol time periods as a quality improvement project. STUDY DESIGN: This is a before and after retrospective cohort study as a quality improvement report examining compliance with a multidisciplinary delivery approach for patients with suspected PAS between 2007 and 2018. This bundle involved a multidisciplinary approach with maternal-fetal medicine, gynecologic oncology, intervention radiology, obstetric anesthesia, neonatology, and blood bank. The primary outcome was incorporation of all six of the components of the bundle into a PAS procedure: (1) betamethasone, (2) gynecologic oncology intraoperative consult, (3) preoperative balloon catheters, (4) cell salvage technology in the operating room, (5) vertical skin incision, and (6) fundal or high transverse hysterotomy. Demographic, delivery, and patient outcome data were also collected. RESULTS: There were 39 patients included in the study, 17 were pre-protocol and 22 were post-protocol. Patients were more likely to have a PAS suspected in the antenatal period during post protocol period (23.5 versus 90.9%, p < .0001), as well as having a placenta previa (35.3 versus 81.8%, p = .003), and receive betamethasone prior to delivery (23.5 versus 86.3%, p < .0001). Patients were delivered at an earlier gestational age in post protocol period (36.8 ± 2.52 versus 33.87 ± 2.4, p = .001). The primary outcome, adherence to all components of the patient-safety bundle, was more likely to occur in the post protocol period (0 versus 40.9%, p < .0001). Maternal and postoperative outcomes were not significantly different between groups. CONCLUSIONS: We have successfully implemented a patient-safety bundle for PAS and have standardized the execution of multidisciplinary management for PAS at our institution.

Characteristics of unplanned hospitalisations among cancer patients in Singapore.

INTRODUCTION: Cancer is a pervasive global problem with significant healthcare utilisation and cost. Emergency departments (EDs) see large numbers of patients with oncologic emergencies and act as "gate-keepers" to subsequent hospital admissions. A proportion of such hospital admissions are rapidly discharged within 2 days and may be potentially avoidable. METHODS: Over a 6-month period, we conducted a retrospective audit of active cancer patients presenting to the ED with subsequent admission to the Department of Medical Oncology. Our aims were to identify independent factors associated with a length of stay ≤2 days; and characterise the clinical and resource needs of these short admissions. RESULTS: Among all medical oncology admissions, 24.4% were discharged within 2 days. Compared to longer stayers, patients with short admissions were significantly younger (P=0.010), had lower National Early Warning Scores (NEWS) (P=0.006), and had a lower proportion of gastrointestinal and hepatobiliary cancers (P=0.005). Among short admissions, common presenting medical problems were infections (n=144, 36.3%), pain (n=116, 29.2%), gastrointestinal complaints (n=85, 21.4%) and respiratory complaints (n=76, 19.1%). These admissions required investigations and treatments already available at the ED. CONCLUSION: Short admissions have low resource needs and may be managed in the ED. This may help save valuable inpatient bed-days and reduce overall healthcare costs.

Routine Blood Tests in Asymptomatic Patients With Indolent Lymphoma Have Limited Ability to Detect Clinically Significant Disease Progression.

PURPOSE: Patients with indolent non-Hodgkin lymphoma (iNHL) undergo regular active surveillance in between treatment periods to detect disease relapse or progression. As part of surveillance, international guidelines recommend regular routine blood testing, which is based on consensus rather than evidence of utility. METHODS: We conducted a retrospective analysis of all patients older than age 16 years diagnosed with grade 1-3A follicular or marginal zone lymphoma between 2008 and 2017 from 2 Australian cancer centers to assess the utility of full blood examination, lactate dehydrogenase, and ß2-microglobulin in detecting progression events, defined as either disease relapse or progression of disease. RESULTS: One hundred eighty patients attended 1,757 outpatient appointments (median follow-up, 36 months). Routine blood tests (RBTs) were performed before 83% of appointments. Seventy-four progression events occurred in 62 patients. Only 2 events (3%) were detected by RBTs alone, both of which occurred in treatment-naïve patients who subsequently developed symptoms within 3 weeks. The remainder of progression events were suspected clinically (88%) or detected by imaging (9%). RBT results were frequently abnormal in asymptomatic patients (19%), with abnormal results leading to either additional investigations or an increased surveillance frequency in 8% of cases. The overall sensitivity and positive predictive value of abnormal RBT results in detecting progression events were 39% and 9%, respectively. CONCLUSION: RBTs have poor performance characteristics and rarely detect clinically significant disease progression or relapse in asymptomatic patients with iNHL.

Microcystic, Elongated, and Fragmented Pattern Invasion in Ovarian Endometrioid Carcinoma: Immunohistochemical Profile and Prognostic Implications.

Microcystic, elongated, and fragmented (MELF) pattern invasion is a poor prognostic indicator in uterine endometrioid carcinoma, but its existence, biology, and prognostic value have not been described in ovarian endometrioid carcinoma. We evaluated cases of ovarian endometrioid carcinoma without synchronous uterine endometrioid carcinoma for MELF and other histologic features. To evaluate tumor biology, we assessed an immunohistochemical profile, including MLH1, PMS2, MSH2, MSH6, ß-catenin, e-cadherin, CK19, and cyclin D1. A retrospective chart review evaluated clinical and demographic features and survival. The Fisher exact test analyzed data. The Kaplan-Meier method assessed overall survival. Forty-two patients met inclusion criteria. MELF was found in 45%. Two MELF cases showed MSH2/MSH6 deficiency and 2 conventional cases showed PMS2 deficiency. Clear cell features were seen exclusively in MELF cases (P-value=0.044). No difference was identified in overall survival, cancer recurrence, serous features, concurrent endometriosis, lymphovascular space invasion, lymph node metastasis, bilaterality of disease, extranodal metastasis, or remainder of immunohistochemical profile. MELF occurs at similar rates in ovarian endometrioid carcinoma and uterine endometrioid carcinoma and can be helpful in defining ovarian endometrioid carcinoma as it proves definitive invasion. Recurrence and overall survival in ovarian endometrioid carcinoma are not affected by MELF. Clear cell features are identified exclusively in MELF cases. Different mismatch repair proteins are lost in MELF compared with conventional ovarian endometrioid carcinomas. Given its association with clear cell features and mismatch repair protein loss, presence of MELF may be useful in clinical decisions regarding surgical staging and Lynch syndrome screening.

Incidental leiomyosarcoma found at the time of cesarean hysterectomy for morbidly adherent placenta.

BACKGROUND: Incidental leiomyosarcoma (LMS) is a rare diagnosis in pregnancy or in the puerperium. To our knowledge, this is the first case reported in the literature of incidental LMS after cesarean hysterectomy for morbidly adherent placenta. CASE: We present a case of a cesarean hysterectomy performed for a suspected morbidly adherent placenta in a patient with three prior cesarean deliveries, an anterior placenta previa and a fundal fibroid. Subsequent pathology identified a LMS on final specimen. The patient declined bilateral oophorectomy and removal of her remaining cervix. No chemotherapy or radiation was given for her presumed stage IB disease. CONCLUSION: An incidental finding of a LMS is infrequent; the risk of recurrence is > 50% even if the sarcoma is removed in its entirety.

Pulmonary Contusion and Traumatic Pneumatoceles in a Platform Diver with Hemoptysis.

BACKGROUND: Injuries in divers resulting purely from impact with the water are uncommon in the published literature. We present a case report of pulmonary contusion in a young diver. CASE REPORT: A young, healthy competitive platform diver landed flat on his back in the water from a dive of 10 meters. He complained of upper back pain and had an episode of hemoptysis after the dive. He was initially observed for 15 hours postinjury, and was discharged when three chest radiographs (CXRs) taken at 1, 7, and 11 hours postinjury did not show significant abnormalities. Thirty-six hours postinjury, the patient experienced repeat hemoptysis and returned to the emergency department, where a fourth CXR performed 43 hours postinjury was normal. A computed tomography (CT) scan revealed pulmonary contusion and traumatic subpleural pneumatoceles. The patient was admitted to the cardiothoracic ward for observation. He recovered well with conservative treatment and was discharged on the fifth day after injury with clearance for air travel. In this patient with a high-energy mechanism of rapid deceleration and hemoptysis at the scene, there may be grounds for performing a CT scan of the thorax at the time of the first presentation, although the CT findings did not change conservative management of this patient. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should recognize that a dive into water may generate sufficient impact to produce a pulmonary contusion. If the patient is clinically well and the CXR results are normal, the decision to initiate a CT scan and subsequent disposition may be based on clinical judgement and institutional practice.

Ossified Dorsal Wrist Ganglion Cyst: A Case Report.

Ganglion cysts are the most common wrist tumors, and 60 -70% originate dorsally from the scapholunate interval. Ossification of these lesions is exceedingly rare, with only one such lesion located in the finger reported in the literature. We present a case of an ossified dorsal wrist ganglion in a 68-year-old woman.

Pathological evaluation of nipple-sparing mastectomies with emphasis on occult nipple involvement: the Weill-Cornell experience with 325 cases.

Nipple-sparing mastectomy (NSM) is an increasingly utilized surgical option in managing breast carcinoma; however, data on malignant involvement of a separately submitted nipple margin are scant. Consecutive NSM, including those performed for therapeutic and prophylactic purposes, over a 4-year period (2007-2011), were studied. A separately submitted nipple margin was evaluated by permanent H&E preparations and via frozen section evaluation whenever requested. 325 consecutive NSM specimens, 208 (64%) therapeutic-NSM, and 117 (36%) prophylactic-NSM were studied. All nipples were clinically unremarkable. 86% (179/208) of nipple margins from therapeutic-NSM and 100% (117/117) from prophylactic-NSM showed no histopathologic abnormality. 14% (29/208) of nipple margins from therapeutic-NSM and no nipple margin from prophylactic-NSM showed malignancy. Frozen section evaluation was performed in 188/325 NSM (58%) with a sensitivity of 64% and specificity of 99%. Central tumor location and stage N2/N3 lymph node status were significantly associated with nipple margin positivity (χ(2) ≤ 0.05). Subsequent nipple resection was performed in 69% (20/29) of nipple margin-positive cases with residual malignancy found in 40% (8/20, including three cases of invasive carcinoma). In a mean follow-up of 33 months, one invasive carcinoma recurred in the "saved" nipple, 36 months after therapeutic-NSM. 14% (29/208) of nipple margins in therapeutic-NSM and no nipple margin (0/117) in prophylactic-NSM showed malignancy. Central tumor location and N2/N3 stage were significantly associated with nipple margin positivity (χ(2) ≤ 0.05).

Proteome profiling of the dimorphic fungus Penicillium marneffei extracellular proteins and identification of glyceraldehyde-3-phosphate dehydrogenase as an important adhesion factor for conidial attachment.

Despite being the most important thermal dimorphic fungus causing systemic mycosis in Southeast Asia, the pathogenic mechanisms of Penicillium marneffei remain largely unknown. By comparing the extracellular proteomes of P. marneffei in mycelial and yeast phases, we identified 12 differentially expressed proteins among which glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and heat shock protein 60 (HSP60) were found to be upregulated in mycelial and yeast phases respectively. Based on previous findings in other pathogens, we hypothesized that these two extracellular proteins may be involved in adherence during P. marneffei-host interaction. Using inhibition assays with recombinant GAPDH (rGAPDH) proteins and anti-rGAPDH sera, we demonstrated that adhesion of P. marneffei conidia to fibronectin and laminin was inhibited by rGAPDH or rabbit anti-rGAPDH serum in a dose-dependent manner. Similarly, a dose-dependent inhibition of conidial adherence to A549 pneumocytes by rGAPDH or rabbit anti-rGAPDH serum was observed, suggesting that P. marneffei GAPDH can mediate binding of conidia to human extracellular matrix proteins and pneumocytes. However, HSP60 did not exhibit similar inhibition on conidia adherence, and neither GAPDH norHSP60 exhibited inhibition on adherence to J774 or THP-1 macrophage cell lines. This report demonstrates GAPDH as an adherence factor in P. marneffei by mediating conidia adherence to host bronchoalveolar epithelium during the early establishment phase of infection.

Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors.

BACKGROUND: Ovarian cancer is the major cause of death from gynaecological malignancy with a 5year survival of only ∼30% due to resistance to platinum and paclitaxel-based first line therapy. Dysregulation of the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) and RAS/extracellular signal-regulated kinase (ERK) pathways is common in ovarian cancer, providing potential new targets for 2nd line therapy. METHODS: We determined the inhibition of proliferation of an extensive panel of ovarian cancer cell lines, encompassing all the major histotypes, by the dual PI3K/mTOR inhibitor PF-04691502 and a MEK inhibitor, PD-0325901. In addition, we analysed global gene expression, mutation status of key PI3K/mTOR and RAS/ERK pathway members and pathway activation to identify predictors of drug response. RESULTS: PF-04691502 inhibits proliferation of the majority of cell lines with potencies that correlate with the extent of pathway inhibition. Resistant cell lines were characterised by activation of the RAS/ERK pathway as indicated by differential gene expression profiles and pathway activity analysis. PD-0325901 suppressed growth of a subset of cell lines that were characterised by high basal RAS/ERK signalling. Strikingly, using PF-04691502 and PD-0325901 in combination resulted in synergistic growth inhibition in 5/6 of PF-04691502 resistant cell lines and two cell lines resistant to both single agents showed robust synergistic growth arrest. Xenograft studies confirm the utility of combination therapy to synergistically inhibit tumour growth of PF-04691502-resistant tumours in vivo. CONCLUSIONS: These studies identify dual targeted inhibitors of PI3K/mTOR in combination with inhibitors of RAS/ERK signalling as a potentially effective new approach to treating ovarian cancer.