A Large Board Pin in the Right Main Bronchus: A Case Report With Review of Literature.

Foreign body (FB) aspiration is one of the most common emergency scenarios in cardiothoracic surgery and ENT unit consultations. We present the case of a 16-year-old male student who inadvertently ingested board pins while enjoying leftover savory. Despite the initial shock, he promptly sought evaluation at the local primary care facility. Remarkably, he remained largely asymptomatic. A subsequent chest radiograph revealed a radiopaque FB lodged in the right main bronchus. Employing a rigid bronchoscope, we successfully extracted the FB, obviating the need for open surgical intervention. What sets this case apart is the unusual combination of a large FB aspiration with minimal symptoms and the absence of internal injury during retrieval.

The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial.

The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

AKT1 interacts with DHX9 to Mitigate R Loop-Induced Replication Stress in Ovarian Cancer.

PARP inhibitor (PARPi)-resistant BRCA-mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Here, we performed a quantitative high-throughput drug combination screen that identified the combination of an ATR inhibitor (ATRi) and an AKT inhibitor (AKTi) as an effective treatment strategy for both PARPi-sensitive and PARPi-resistant BRCAm HGSOC. The ATRi and AKTi combination induced DNA damage and R loop-mediated replication stress (RS). Mechanistically, the kinase domain of AKT1 directly interacted with DHX9 and facilitated recruitment of DHX9 to R loops. AKTi increased ATRi-induced R loop-mediated RS by mitigating recruitment of DHX9 to R loops. Moreover, DHX9 was upregulated in tumors from patients with PARPi-resistant BRCAm HGSOC, and high coexpression of DHX9 and AKT1 correlated with worse survival. Together, this study reveals an interaction between AKT1 and DHX9 that facilitates R loop resolution and identifies combining ATRi and AKTi as a rational treatment strategy for BRCAm HGSOC irrespective of PARPi resistance status. SIGNIFICANCE: Inhibition of the AKT and ATR pathways cooperatively induces R loop-associated replication stress in high-grade serous ovarian cancer, providing rationale to support the clinical development of AKT and ATR inhibitor combinations. See related commentary by Ramanarayanan and Oberdoerffer, p. 793.

BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor-resistant BRCA-mutant ovarian cancer.

Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene (BRCA)-mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA-mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with BRCA-mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase (BLM) and cyclin E1 (CCNE1) overexpression or copy number gain/amplification were seen in patients who derived durable benefit from CHK1i. BRCA reversion mutation in previously PARPi-treated BRCA-mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork-related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA-mutant HGSC.

Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer.

Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a major advance in ovarian cancer, now as a treatment and as a maintenance therapy in the upfront and recurrent settings. However, patients often develop resistance to PARPis, underlining the importance of dissecting resistance mechanisms. Here, we report different dosing/timing schemes of PARPi treatment in BRCA2-mutant PEO1 cells, resulting in the simultaneous development of distinct resistance mechanisms. PARPi-resistant variants PEO1/OlaJR, established by higher initial doses and short-term PARPi treatment, develops PARPi resistance by rapidly restoring functional BRCA2 and promoting drug efflux activity. In contrast, PEO1/OlaR, developed by lower initial doses with long-term PARPi exposure, shows no regained BRCA2 function but a mesenchymal-like phenotype with greater invasion ability, and exhibits activated ATR/CHK1 and suppressed EZH2/MUS81 signaling cascades to regain HR repair and fork stabilization, respectively. Our study suggests that PARPi resistance mechanisms can be governed by treatment strategies and have a molecular basis on BRCA2 functionality. Further, we define different mechanisms that may serve as useful biomarkers to assess subsequent treatment strategies in PARPi-resistant ovarian cancer.

Mitral valve repair in chronic severe mitral regurgitation: short-term results and analysis of mortality predictors.

INTRODUCTION: Mitral valve repair is the accepted treatment for mitral regurgitation (MR) but lack of resources and socioeconomic concerns delay surgical referral and intervention in developing countries. We evaluated immediate and short-term results of mitral valve repair for non-ischemic MR at our centre and aimed to identify the predictors of in-hospital and follow-up mortality. MATERIALS AND METHODS: The study was conducted at a tertiary-level hospital in South India. All patients >18 years with severe non-ischemic MR who underwent mitral valve repair over a period of 6 years were included. Perioperative data was collected from hospital records and follow-up data was obtained by prospective methods. RESULTS: There were 244 patients (170 males). Most of the patients were in the age group 31-60 years (76.6%). Aetiology of MR was degenerative (n = 159; 65.2%), rheumatic (n = 34; 13.9%), structural (n = 42; 17.2%), or miscellaneous (n = 9; 3.7%). All patients underwent ring annuloplasty with various valve repair techniques. One hundred patients (44.7%) underwent additional cardiac procedures. At discharge, MR was moderate in 4 patients; the rest had no or mild MR. The mean hospital stay of survivors was 7.1 days (SD 2.52, range 5-25 days). There were 9 in-hospital deaths (3.68%) and 10 deaths during follow-up (4.2%). The mean follow-up period was 1.39 years, complete for 87.6%. Pre-operative left ventricle ejection fraction (LVEF) <60% (p = 0.04) was found to be significantly associated with immediate mortality. Logistic regression analysis detected age (p = 0.019), female sex (p = 0.015), and left ventricular (LV) dysfunction at discharge (p = 0.025) to be significantly associated with follow-up mortality. CONCLUSION: Pre-operative LV dysfunction was identified as a significant risk factor for in-hospital mortality. Female sex, age greater than 45 years, and LV dysfunction at discharge were found to be significantly associated with follow-up mortality. Hence, it is important to perform mitral valve repair in severe regurgitation patients before significant LV dysfunction sets in for a better outcome.

Targeting the PI3K/mTOR Pathway Augments CHK1 Inhibitor-Induced Replication Stress and Antitumor Activity in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in industrialized countries and has limited treatment options. Targeting ataxia-telangiectasia and Rad3-related/cell-cycle checkpoint kinase 1 (CHK1)-mediated S-phase and G2-M-phase cell-cycle checkpoints has been a promising therapeutic strategy in HGSOC. To improve the efficacy of CHK1 inhibitor (CHK1i), we conducted a high-throughput drug combination screening in HGSOC cells. PI3K/mTOR pathway inhibitors (PI3K/mTORi) showed supra-additive cytotoxicity with CHK1i. Combined treatment with CHK1i and PI3K/mTORi significantly attenuated cell viability and increased DNA damage, chromosomal breaks, and mitotic catastrophe compared with monotherapy. PI3K/mTORi decelerated fork speed by promoting new origin firing via increased CDC45, thus potentiating CHK1i-induced replication stress. PI3K/mTORi also augmented CHK1i-induced DNA damage by attenuating DNA homologous recombination repair activity and RAD51 foci formation. High expression of replication stress markers was associated with poor prognosis in patients with HGSOC. Our findings indicate that combined PI3K/mTORi and CHK1i induces greater cell death in HGSOC cells and in vivo models by causing lethal replication stress and DNA damage. This insight can be translated therapeutically by further developing combinations of PI3K and cell-cycle pathway inhibitors in HGSOC. SIGNIFICANCE: Dual inhibition of CHK1 and PI3K/mTOR pathways yields potent synthetic lethality by causing lethal replication stress and DNA damage in HGSOC, warranting further clinical development.

Chest wall reconstruction: success of a team approach-a 12-year experience from a tertiary care institution.

BACKGROUND: The thoracic cavity was considered as a forbidden area in the past and anyone attempting to meddle with it was expected to be doomed. But the past several decades have seen a marked improvement in the management and reconstruction of complex chest wall defects. This study was undertaken to review our experience in chest wall reconstruction during the past 12 years and to stress upon the importance of a multidisciplinary team approach to this complex problem. METHODS: After obtaining the necessary clearance from institutional ethics committee, we did a retrospective review of all case records of chest wall reconstructions (CWR) performed in our institution during a 12-year period from May 2005 to September 2016. Patient characteristics, co-morbidities, operative data and post-operative complications and outcomes were reviewed. RESULTS: During the study period, a total of 32 patients underwent CWR. All patients were assessed, planned, operated and managed by a team consisting of thoracic surgeons, plastic surgeons, intensivists and pulmonologists. Patients were in the age group of 14-72 with a male:female ratio of 15:17. Indications for CWR were neoplasms (n = 13-40.62%), post-sternotomy wound dehiscence (n = 12-37.5%), osteoradionecrosis (n = 4-12.5%), tuberculosis (n = 2-6.25%) and osteomyelitis rib (1/32-3.125%). Inflammatory defects were mostly closed with soft tissue alone whereas skeletal stabilisation with soft tissue cover was required in tumour resections. All were pedicled flaps, the most common being pectoralis major (PM) muscle flap (n = 12). Others include latissimus dorsi (LD) muscle (n = 9); rectus abdominis (RA) muscle (n = 2); transverse rectus abdominis musculocutaneous flap (TRAM) (n = 2), deltopectoral (DP) (n = 1), omentum (n = 3) and breast flap (n = 3). Post-operative complications include wound dehiscence (12%), wound infection (21%) and recurrent sinus formation (7%). One partial flap failure was recorded. Post-operative mortality was 3%. CONCLUSION: Chest wall reconstruction is a complex procedure and each defect needs an individualised approach for optimum outcome. Extensive chest wall resections can be safely undertaken with the support of the reconstructive surgeon and with good critical care back up.

Clinical outcomes of prexasertib monotherapy in recurrent BRCA wild-type high-grade serous ovarian cancer involve innate and adaptive immune responses.

BACKGROUND: Preclinical data suggest cell cycle checkpoint blockade may induce an immunostimulatory tumor microenvironment. However, it remains elusive whether immunomodulation occurs in the clinical setting. To test this, we used blood and fresh tissue samples collected at baseline and post therapy from a phase II trial of the cell cycle checkpoint 1 inhibitor (CHK1i) prexasertib in recurrent ovarian cancer. METHODS: Paired blood samples and fresh core biopsies, taken before treatment was started at baseline (cycle 1 day 1 (C1D1)) and post second dose on day 15 of cycle 1 (C1D15), were collected. To evaluate changes in the immune responses after treatment, multiparametric flow cytometry for DNA damage markers and immune cell subsets was performed on paired blood samples. RNA sequencing (RNAseq) of paired core biopsies was also analyzed. Archival tissue immune microenvironment was evaluated with immunohistochemistry. All correlative study statistical analyses used two-sided significance with a cut-off of p=0.05. RESULTS: Flow cytometric analysis showed significantly increased γ-H2AX staining after CHK1i treatment, accompanied by increased monocyte populations, suggestive of an activated innate immune response (median 31.6% vs 45.6%, p=0.005). Increased expressions of immunocompetence marker HLA-DR (Human Leukocyte Antigen DR antigen) on monocytes and of TBK1, a marker of STING (stimulator of interferon genes) pathway activation, in biopsies were associated with improved progression-free survival (PFS) (9.25 vs 3.5 months, p=0.019; 9 vs 3 months, p=0.003, respectively). Computational analysis of RNAseq data indicated increased infiltration of tumor niches by naïve B-cells and resting memory T-cells, suggestive of a possibly activated adaptive immune response, and greater T-reg infiltration after treatment correlated with worse PFS (9.25 vs 3.5 months, p=0.007). An immunosuppressive adaptive immune response, perhaps compensatory, was also observed on flow cytometry, including lymphodepletion of total peripheral CD4+ and CD8+T cells after CHK1i and an increase in the proportion of T-regs among these T-cells. Additionally, there was a trend of improved PFS with greater tumor-infiltrating lymphocytes (TILs) in archival tissues (13.7 months >30% TILs vs 5.5 months ≤30% TILs, p=0.05). CONCLUSION: Our study demonstrates that a favorable clinical response in high-grade serous ovarian carcinoma patients treated with CHK1i is possibly associated with enhanced innate and adaptive immunity, requiring further mechanistic studies. It is supportive of current efforts for a clinical development strategy for therapeutic combinations with immunotherapy in ovarian cancer.

Resistance to the CHK1 inhibitor prexasertib involves functionally distinct CHK1 activities in BRCA wild-type ovarian cancer.

High grade serous ovarian cancer (HGSOC) is a fatal gynecologic malignancy in the U.S. with limited treatment options. New therapeutic strategies include targeting of the cell cycle checkpoints, e.g., ATR and CHK1. We recently reported a promising clinical activity of the CHK1 inhibitor (CHK1i) prexasertib monotherapy in BRCA wild-type (BRCAwt) HGSOC patients. In this study, biopsies of treated patients and cell line models were used to investigate possible mechanisms of resistance to CHK1i. We report that BRCAwt HGSOC develops resistance to prexasertib monotherapy via a prolonged G2 delay induced by lower CDK1/CyclinB1 activity, thus preventing cells from mitotic catastrophe and cell death. On the other hand, we noted CHK1's regulation on RAD51-mediated homologous recombination (HR) repair was not altered in CHK1i-resistant cells. Therefore, CHK1i sensitizes CHK1i-resistant cells to DNA damaging agents such as gemcitabine or hydroxyurea by inhibition of HR. In summary, our results demonstrate new mechanistic insights of functionally distinct CHK1 activities and highlight a potential combination treatment approach to overcome CHK1i resistance in BRCAwt HGSOC.

A Phase II Single Arm Pilot Study of the CHK1 Inhibitor Prexasertib (LY2606368) in BRCA Wild-Type, Advanced Triple-Negative Breast Cancer.

LESSONS LEARNED: Monotherapy with prexasertib demonstrated modest activity in BRCA wild-type, recurrent triple-negative breast cancer, highlighting the unmet need for combination treatment strategies. Neutropenia, anemia, and thrombocytopenia are common with the use of prexasertib but are manageable with supportive care measures. Prophylactic use of granulocyte colony stimulating factor should be considered to avoid dose reductions or treatment delays. Pharmacodynamic studies showed prexasertib treatment induced DNA damage in peripheral immune cells. BACKGROUND: Cell cycle checkpoint kinase 1 (CHK1) is a major G2/M cell cycle regulator in tumors with p53 dysfunction, such as triple-negative breast cancer (TNBC). We hypothesized the second-generation CHK1 inhibitor, prexasertib, would yield clinical activity in sporadic TNBC. METHODS: This single arm, phase II trial evaluated prexasertib at 105 mg/m2 IV every 2 weeks in patients with metastatic/recurrent TNBC. The primary endpoint was overall response rate (ORR). RESULTS: All nine patients enrolled were germline BRCA wild-type (BRCAwt) and had at least one prior treatment. One partial response (PR) was observed (ORR of 11.1%). Four patients experienced stable disease. The median progression-free survival (PFS) was 86 days (range 17 to 159 days). Grade 3/4 treatment-related adverse events included afebrile neutropenia (n = 8; 88.9%), anemia (n = 3; 33.3%), and thrombocytopenia (n = 1; 11.1%). Pharmacodynamic studies showed prexasertib treatment induced DNA damage in peripheral immune cells and demonstrated a decrease in activated/reinvigorated CD8 T cells; however, the one patient with a PR showed evidence of T-cell recovery. CONCLUSION: Prexasertib monotherapy had modest clinical efficacy in BRCAwt TNBC. Further studies of prexasertib in combination with other agents are needed.

Combination of PARP Inhibitor Olaparib, and PD-L1 Inhibitor Durvalumab, in Recurrent Ovarian Cancer: a Proof-of-Concept Phase II Study.

PURPOSE: Preclinical studies suggest PARP inhibition (PARPi) induces immunostimulatory micromilieu in ovarian cancer thus complementing activity of immune checkpoint blockade. We conducted a phase II trial of PARPi olaparib and anti-PD-L1 durvalumab and collected paired fresh core biopsies and blood samples to test this hypothesis. PATIENTS AND METHODS: In a single-center, proof-of-concept phase II study, we enrolled women aged ≥18 with recurrent ovarian cancer. All patients were immune checkpoint inhibitor-naïve and had measurable disease per RECISTv1.1, ECOG performance status 0-2, and adequate organ and marrow function. Patients received olaparib 300 mg twice daily and durvalumab 1,500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoint was overall response rate (ORR). Secondary objectives were safety and progression-free survival (PFS). Translational objectives included biomarker evaluation for relationships with clinical response and immunomodulatory effects by treatment. RESULTS: Thirty-five patients with ovarian cancer [median, four prior therapies (IQR, 2-5.5), predominantly platinum-resistant (86%), BRCA wild-type (77%)] received at least one full cycle of treatment. ORR was 14% [5/35; 95% confidence interval (CI), 4.8%-30.3%]. Disease control rate (PR+SD) was 71% (25/35; 95% CI, 53.7%-85.4%). Treatment enhanced IFNγ and CXCL9/CXCL10 expression, systemic IFNγ/TNFα production, and tumor-infiltrating lymphocytes, indicating an immunostimulatory environment. Increased IFNγ production was associated with improved PFS [HR, 0.37 (95% CI, 0.16-0.87), P = 0.023], while elevated VEGFR3 levels were associated with worse PFS (HR, 3.22 (95% CI, 1.23-8.40), P = 0.017]. CONCLUSIONS: The PARPi and anti-PD-L1 combination showed modest clinical activity in recurrent ovarian cancer. Our correlative study results suggest immunomodulatory effects by olaparib/durvalumab in patients and indicate that VEGF/VEGFR pathway blockade would be necessary for improved efficacy of the combination.

Patients with BRCA mutated ovarian cancer may have fewer circulating MDSC and more peripheral CD8+ T cells compared with women with BRCA wild-type disease during the early disease course.

Immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are associated with immunologic tolerance and poor prognosis in ovarian cancer (OvCa). We hypothesized that women with germline BRCA1 and BRCA2 mutation-associated (gBRCAm) OvCa would have fewer circulating immunosuppressive immune cells compared to those with BRCA wild-type (BRCAwt) disease during their early disease course (<5 years post-diagnosis) where gBRCAm is a favorable prognostic factor. We collected and viably froze peripheral blood mononuclear cells (PBMCs) from patients with recurrent OvCa olaparib clinical trials (NCT01445418/NCT01237067). Immune subset analyses were performed using flow cytometry for Tregs, exhausted CD8+ T cells, monocytes and MDSCs. Functional marker expression, including cytotoxic T lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain 3 (TIM-3) and programmed cell death protein 1 (PD-1) was evaluated. Data were analyzed using FlowJo. Pretreatment PBMCs were collected from 41 patients (16 gBRCAm/25 BRCAwt). The percentage of MDSCs among viable CD45+ PBMC was lower in gBRCAm OvCa compared with BRCAwt OvCa (median 0.565 vs. 0.93%, P=0.0086) but this difference was not seen in those women >5 years post-diagnosis. CD8+ T cells among viable CD45+ PBMCs and CTLA-4+/CD8+ T cells were higher in gBRCAm carriers than patients with BRCAwt, in particular for those <5 years post-diagnosis (median 20.4 vs. 9.78%, P=0.031 and median MFI 0.19 vs. 0.22, P=0.0074, respectively). TIM-3 expression on Tregs was associated with poor progression-free survival, independent of gBRCAm status (P<0.001). Our pilot data suggested that patients with gBRCAm OvCa may have fewer circulating MDSCs but higher CD8+ T cells in PBMCs during their early disease course. This may contribute to the observed survival benefit for these women in their first post-diagnosis decade.

Brucellosis After Cardiac Transplantation.

Brucellosis is being increasingly recognized after solid organ transplantation but has not been reported after orthotopic heart transplantation. We present the case of a 51-year-old farmer who underwent orthotopic heart transplantation and was readmitted after 3 months in a severely immunosuppressed state with significant nonspecific complaints. He posed a diagnostic and management dilemma to all disciplines, but finally turned out to be harboring Brucella infection. He responded well to medical management and was discharged in a stable clinical status. Although rare, brucellosis should be included in the investigative workup for nonspecific symptoms after cardiac transplantation.

Should all tubercular cavities be left alone? Lessons from a heart transplant.

Fungal infection after solid organ transplantation poses a diagnostic and therapeutic challenge. We present the case of a 50-year-old man who underwent orthotopic heart transplantation for dilated cardiomyopathy with a history of treated pulmonary tuberculosis 10 years pre-transplant. One year post-transplantation, he was admitted with recurrent productive cough and was evaluated to have intracavitory aspergillosis of the lung. He was started on medical therapy with reduction in immunosuppression, but succumbed later with allograft rejection and multiorgan failure. Management of invasive aspergillosis in immunocompromised host is a real challenge. Management protocol should be individualised.

"Not all bullae are synonymous with COPD"-a rare congenital anomaly described.

Hyperlucent areas with thin walls and absent vascular markings in chest X ray are described as radiological findings of a bullae. We present the case of an adult male referred for coronary revascularisation and bullectomy in the right lung. A non-smoker, without any significant past medical history, made us think of bronchial atresia. He was planned for coronary artery bypass grafting with close follow-up of lung anomaly. Clinicians should be aware of this entity in non-smokers with unilateral bullous lesion and calcification as other close clinical differentials warrant aggressive medical management.

Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept phase 2 study.

BACKGROUND: High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease. METHODS: In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status score 0-2, and adequate haematological, renal, hepatic, and bone-marrow function. Patients received intravenous prexasertib 105 mg/m2 administered over 1 h every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of investigator-assessed tumour response, based on RECIST version 1.1, was assessed per protocol (assessable patients who had undergone CT imaging at baseline and attended at least one protocol-specified follow-up) and by intention to treat. The final analysis of this cohort of patients with BRCA wild-type high-grade serous ovarian carcinoma is reported here. This ongoing trial is registered with ClinicalTrials.gov, number NCT02203513, and continues to enrol patients for the BRCA-mutated ovarian cancer cohort. FINDINGS: Between Jan 20, 2015, and Nov 2, 2016, we enrolled 28 women with a median age of 64 years (IQR 58·0-69·5) who had previously received a median of 5·0 (IQR 2·5-5·0) systemic therapies. Most patients (22 [79%]) had platinum-resistant or platinum-refractory disease. All women received at least one dose of prexasertib, but four (14%) of 28 patients were not assessable for RECIST response. Eight (33%, 95% CI 16-55) of 24 patients assessable per protocol had partial responses. In the intention-to-treat population, eight (29%, 95% CI 13-49) of 28 had a partial responses. The most common (in >10% patients) grade 3 or 4 treatment-emergent adverse events were neutropenia in 26 (93%) of 28 patients, reduced white blood cell count in 23 (82%), thrombocytopenia in seven (25%), and anaemia in three (11%). Grade 4 neutropenia was reported in 22 (79%) patients after the first dose of prexasertib and was transient (median duration 6 days [IQR 4-8]) and recovered without growth-factor support in all cases. The treatment-related serious adverse event of grade 3 febrile neutropenia was reported in two (7%) patients. One patient died during the study due to tumour progression. INTERPRETATION: Prexasertib showed clinical activity and was tolerable in patients with BRCA wild-type high-grade serous ovarian carcinoma. This drug warrants further development in this setting, especially for patients with platinum-resistant or platinum-refractory disease. FUNDING: Intramural Research Program of the National Institutes of Health and National Cancer Institute.