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Respiratory viral infections are a leading cause of disease worldwide. A variety of respiratory viruses produce infections in humans with effects ranging from asymptomatic to life-treathening. Standard surveillance systems typically only target severe infections (ED outpatients, hospitalisations, deaths) and fail to track asymptomatic or mild infections. Here we performed a large-scale community study across multiple age groups to assess the pathogenicity of 18 respiratory viruses. We enrolled 214 individuals at multiple New York City locations and tested weekly for respiratory viral pathogens, irrespective of symptom status, from fall 2016 to spring 2018. We combined these test results with participant-provided daily records of cold and flu symptoms and used this information to characterise symptom severity by virus and age category. Asymptomatic infection rates exceeded 70% for most viruses, excepting influenza and human metapneumovirus, which produced significantly more severe outcomes. Symptoms were negatively associated with infection frequency, with children displaying the lowest score among age groups. Upper respiratory manifestations were most common for all viruses, whereas systemic effects were less typical. These findings indicate a high burden of asymptomatic respiratory virus infection exists in the general population.

Background Epithelial ovarian carcinoma is the main cause of death from gynaecological cancers in the western world. The initial response rate to the frontline therapy is high. However, the prognosis of persistent and recurrent disease remains poor. During the two past decades, a new therapeutic approach to peritoneal carcinomatosis has been developed, combining maximal cytoreductive effort with hyperthermic intraperitoneal chemotherapy (HIPEC). Methods A retrospective, multicentric study of 246 patients with recurrent or persistent ovarian cancer, treated by cytoreductive surgery and HIPEC in two French centers between 1991 and 2008, was performed. Results An optimal cytoreductive surgery was possible in 92.2 % of patients. Mortality and morbidity rates were 0.37 % and 11.6 %, respectively. The overall median survival was 48.9 months. There was no significant difference in overall survival in patients with persistent or recurrent disease. In multivariate analysis, performance status was a significant prognostic factor in patients with extensive peritoneal carcinomatosis (peritoneal cancer index >10). Conclusions Salvage therapy combining optimal cytoreductive surgery and HIPEC is feasible and may achieve long-term survival in highly selected patients with recurrent ovarian carcinoma, including those with platinum resistant disease, with acceptable morbidity.

ObjectivesPatterns of recurrence on PARP inhibitor maintenance therapy are unclear and may affect treatment choices for subsequent therapy, including secondary cytoreductive surgery (SCS). This analysis of PRIMA/ENGOT-OV26/GOG-3012 evaluated patterns of recurrence on niraparib maintenance therapy.MethodsThis post hoc subgroup analysis included 314 patients treated with niraparib maintenance monotherapy following first-line chemotherapy and who had no lesions identified by CT/MRI (or by investigator assessment) at baseline. Number and site(s) of initial recurrent lesions at the time of investigator-assessed RECIST-defined progressive disease (PD) were evaluated.ResultsAs of the primary data cut, May 17, 2019, with a median follow-up of 13.8 months (range <1–28), 141/314 (45%) patients developed investigator-assessed PD, with an average 1.9 (standard deviation 0.9) lesions at PD. At the time of recurrence, 62 patients (44%) had 1 lesion, 46 (33%) had 2 lesions, 24 (17%) had 3 lesions, and 9 (6%) had 4–5 lesions. The five most common sites with ≥1 lesion at PD were the peritoneum (n=45), lymph nodes (n=36), liver (n=34), other (n=26), and pelvis (n=20).ConclusionsFor patients who received niraparib maintenance monotherapy after first-line chemotherapy and had no lesions at baseline, <50% had recurrent disease after a median 13.8 months of follow-up and >75% of patients with recurrence progressed in 1–2 sites. Prospective evaluation is required to determine whether patients with oligoprogressive disease have improved outcomes with local therapies, like SCS, in addition to systemic therapy.Funding: GSK (NCT02655016). Editorial support provided by Fishawack Health, funded by GSK.

Breast cancer (BC) is the most common female malignancy in the world and almost one third of cases occur after 70 years of age. Optimal management of BC in the elderly is a real challenge and requires a multidisciplinary approach, mainly because the elderly population is heterogeneous. In this review, we describe the various possibilities of treatment for localized or metastatic BC in an aging population. We provide an overview of the comprehensive geriatric assessment, surgery, radiotherapy, and adjuvant therapy for early localized BC and of chemotherapy and targeted therapies for metastatic BC. Finally, we attempt to put into perspective the necessary balance between the expected benefits and risks, especially in the adjuvant setting.

Background: The main objective of the present study was to establish the relationships between CA-125 kinetics and tumour size changes during treatment. Methods: The data from the CALYPSO-randomised phase III trial, comparing two platinum-based regimens in recurrent ovarian cancer (ROC) patients, was randomly split into a ‘learning data set’ to estimate model parameters and a ‘validation data set’ to validate model performances. A kinetic–pharmacodynamic semi-mechanistic model was built to describe tumour size and CA-125 kinetics during chemotherapy. The ability of the model to predict tumour response induced by chemotherapy, based on CA-125 values, was assessed. Results: Data from 535 ROC patients were used to model CA-125 kinetics and tumour size changes during the first 513 days after treatment initiation. Using the validated model, we could predict with accuracy the tumour size changes induced by chemotherapy based on the baseline imaging assessment and longitudinal CA-125 values (mean prediction error: 0.3%, mean absolute prediction error: 10.6%). Conclusions: Using a semi-mechanistic model, the dynamic relationships between tumour size changes and CA-125 kinetics induced by chemotherapy were established in ROC patients. A modelling approach allowed CA-125 to be assessed as a biomarker for tumour size dynamics, to predict treatment efficacy for research and clinical purposes.

Background: As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel. Methods: Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mg m −2 q3w, paclitaxel 80 mg m −2 every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175 mg m −2 q3w. The primary endpoint was safety/tolerability. Results: A total of 116 patients received saracatinib 125 ( N =20), 175 ( N =44), 225 ( N =40), 250 ( N =9), or 300 mg ( N =3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade ⩾3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; ⩾225 mg, 33%), and grade ⩾3 neutropenia occurred more commonly at doses ⩾225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w. Conclusion: Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials.

Introduction/BackgroundNiraparib improves progression-free survival (PFS) in patients (pts) with newly diagnosed advanced ovarian cancer after 1st-line (1L) platinum-based chemotherapy (CT). We report the efficacy of niraparib in pts by biomarker status.MethodologyThis double-blind, placebo (PBO)-controlled, phase 3 study randomized 733 pts with newly diagnosed advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete or partial response (CR or PR) to 1L platinum-based CT. Stratification factors were best response to the 1L CT (CR/PR), receipt of neoadjuvant CT (yes/no), and homologous recombination status (deficient/proficient/not determined). Pts received niraparib or PBO once daily. The primary endpoint of PFS assessed by blinded independent central review was analyzed using a stratified Cox proportional hazards model and hierarchically tested in homologous recombination deficient pts, then the overall population.ResultsOf 733 randomized pts (niraparib, 487; PBO, 246), 373 (51%) were homologous recombination deficient (niraparib, 247; PBO, 126) and 249 (34%) were homologous recombination proficient (niraparib, 169; PBO, 80). Overall, 35% had stage IV disease, 67% received NACT, and 31% had a PR to 1L CT. Niraparib-treated pts in all the biomarkers groups had a statistically significant and clinically meaningful benefit in PFS (table 1). The most common grade ≥3 adverse events were anemia (31%), thrombocytopenia (29%), and neutropenia (13%).Abstract – Table 1Disease characteristicsHazard ratio (95% CI)P ValueOverall0.62 (0.502–0.755)<0.0001Homologous recombination deficient0.43 (0.310–0.588)<0.0001BRCAmut0.40 (0.265–0.618)<0.0001BRCAwt0.50 (0.305–0.831)0.0064Homologous recombination proficient0.68 (0.492–0.944)0.0203ConclusionNiraparib improved PFS as evidenced by reduction in the risk of recurrence or death due to any cause in the overall population of advanced ovarian cancer. No new safety signals were identified.CI=confidence interval; mut=mutated; wt=wild typeDisclosureAMG: Consulting: AstraZeneca, TESARO, Roche, Pharmamar, Clovis, Merck, Genmab, ImmunoGen, Oncoinvent AS BP, RDC: Advisory: TESARO IV: Personal: Advaxis, Eisai, MSD Belgium, Roche NV, Genmab, Roche, Pharmamar, Millennium Pharmaceuticals, Clovis, Astrazeneca NV, Tesaro, Immunogen, Sotio. Grants: Amgen, Stichting tegen Kanker, Roche. Contracted Research: Oncoinvent AS, Genmab WG: Consulting: TESARO MM: Leadership/Other ownership: Karyopharm Therapeutics, Sera Prognostics. Personal Fees: Roche, AstraZeneca, Clovis, Pfizer, TESARO, Genmab, BioCad, Sotio, Geneos Therapeutics, Merck, Oncology Venture, Seattle Genetics, Sera Prognostics, Takeda, Zailab. Grants: AstraZeneca, Clovis, Pfizer, TESARO, Boehringer Ingelheim CCM, PH, KHB, KJ, CGAV, BL, AFH, MJR-P, WHB, IB: none DL: Personal: AstraZeneca, Clovis, Genmab, Immunogen, Pharma Mar SA, Amgen, Merck. Grants: Pharma Mar SA, Merck GF: Personal: TESARO, AstraZeneca, Clovis, Roche, Bristol-Meyers Squibb, MSD, Pfizer, Novartis. Grants: AstraZeneca, Roche AR: Research funding/Advisory role: Pharmamar, Roche, Eisai,AstraZeneca, TESARO RGM: Research: Angle PLC. Consulting: Fujirebio Diagnostics REO: Advisory: Clovis, TESARO, GlaxoSmithKline FB: Advisory: TESARO, Clovis, Agenus, Merck, Eisai. Grant: Clovis, Merck, Eisai, Immunogen. Lecture: CEC Oncology MPBG: Lecture/Advisory board: TESARO, AstraZeneca, Roche, Clovis, Pharmamar, MSD. MSS: Personal: TESARO, Merck, Astra Zeneca, Clovis, Pacira Pharamceuticals. Grant: TESARO GM: Personal: AstraZeneca, TESARO. Non-Financial Support: TESARO, Roche. BJM: Speaker bureau, Grant: TESARO KS, IM, YL, DG: TESARO employee.

Background: In low-risk gestational trophoblastic neoplasia (GTN) patients, a predictive marker for early identification of methotrexate (MTX) resistance would be useful. We previously demonstrated that kinetic modelling of human chorionic gonadotrophin (hCG) measurements could provide such a marker. Here we validate this approach in a large independent patient cohort. Methods: Serum hCG measurements of 800 low-risk GTN patients treated with MTX were analysed. The cohort was divided into Model and Test data sets. hCG kinetics were described from initial treatment day to day 50 using: ‘(hCG(time))=hCG0*exp(– k *time)+hCGres’, where hCGres is the modelled residual production, hCG0 is the baseline hCG level, and k is the rate constant. HCGres-predictive value was investigated against previously reported predictors of MTX resistance. Results: Declining hCG measurements were well fitted by the model. The best discriminator of MTX resistance in the Model data set was hCGres, categorised by an optimal cut-off value of >20.44 IU l −1 : receiver-operating characteristic (ROC) area under the curve (AUC)=0.87; Se=0.91; Sp=0.83. The predictive value of hCGres was reproducible using the Test data set: ROC AUC=0.87; Se=0.88; Sp=0.86. Multivariate analyses revealed hCGres as a better predictor of MTX resistance (HR=1.01, P <0.0001) and MTX failure-free survival (HR=13.25, P <0.0001) than other reported predictive factors. Conclusion: hCGres, a modelled kinetic parameter calculated after fully dosed three MTX cycles, has a reproducible value for identifying patients with MTX resistance.

Peritoneal carcinomatosis has been regarded as a lethal clinical entity. Recently, aggressive treatments combining intraperitoneal chemohyperthermia (IPCH) with cytoreductive surgery have resulted in long-term survival in selected patients. The aim of this trial was to analyze the mortality and morbidity of 216 consecutive treatments of peritoneal carcinomatosis by IPCH by using a closed abdominal procedure combined with cytoreductive surgery. Between February 1989 and August 2001, 207 patients who underwent 216 IPCH procedures using a closed abdominal procedure with mitomycin C, cisplatin, or both were prospectively studied. The postoperative mortality and morbidity rates were 3.2% and 24.5%, respectively. The most frequent complications were digestive fistula (6.5%) and hematological toxicity (4.6%). Morbidity was statistically linked with the carcinomatosis stage (P =.016), the duration of surgery (P =.005), and the number of resections and peritonectomy procedures (P =.042). Duration of surgery and carcinomatosis stage were the most common predictors of morbidity. The frequency of complications after IPCH and cytoreductive surgery was mainly associated with the carcinomatosis stage and the extent of the surgical procedure. The IPCH closed abdominal procedure has shown an acceptable frequency of adverse events.

The aim of this study was to evaluate antitumor effects of cyclooxygenase-2 inhibitors in breast carcinoma and their ability to act synergistically with aromatase inhibitors (AIs). Postmenopausal metastatic breast cancer patients without previous adjuvant AI treatment received exemestane 25 mg/days plus either celecoxib 400 mg twice daily or placebo. The primary endpoint was progression-free survival (PFS). This trial was prematurely terminated ( N  = 157 of 342 planned) after cardiovascular toxicity was reported in other celecoxib trials. Although no PFS difference was observed between the two arms (9.8 months for both, P  = 0.72), a trend favoring celecoxib was observed in 60 tamoxifen-resistant patients (9.6 vs. 5.1 months; P  = 0.14) and in 126 patients treated ≥3 months before study termination (12.2 vs. 9.8 months; P  = 0.09). No severe adverse events were reported. Cyclooxygenase-2 inhibitors seemingly contribute to reverse endocrine resistance in breast cancer patients, although further study is necessary to allow development of a new therapeutic strategy.