Correlation of diaphragm surgical findings with preoperative CT scans in ovarian cancer

Correlation of diaphragm surgical findings in ovarian cancer patients with and without diaphragm metastases with pre-operative CT diaphragm findings to assess sensitivity and specificity for diaphragm disease. Material and Methods: A retrospective study of 120 ovarian cancer patients (60 with and 60 without diaphragm metastases at surgery), FIGO Stage IIIC or IV, undergoing cytoreductive surgery at Mayo Clinic, Arizona, between January 2000 and October 2014. All patients had preoperative imaging with CT scan of abdomen and pelvis including the lower lung fields. CTs were not reviewed retrospectively. Results: Among 60 patients with diaphragm metastases, preoperative CTs were positive for diaphragm disease in 17 patients, with a sensitivity rate of 28% (CI 95%: 0.17-0.41). All 60 patients with no diaphragm metastases had negative CTs, with a specificity of 100% (CI 95%: 94.0%-100%). When analyzed by lesion size, CTs were negative in 66.7-80% of patients with diaphragm lesions ranging from 1-15 mm. There was a trend towards increased detection rate with increasing size of lesions, but it did not reach significance (p = 0.529). CT detection rate for single metastatic lesion was 18.2% (6/33) and for multiple lesions it was 25.9% (7/27). There was no difference for CT identification of right, left, or bilateral metastases (p = 0.399). The sensitivity and specificity of CT for pleural effusion was 100% (CI 95%: 72.2%-100%) and 88% (CI 95%: 76.2%- 94.4%), respectively. The area under the receiver operating characteristic (ROC) curve was 0.680 (CI 95%: 55.3%-72.2%) for CT detection of diaphragm metastases and 0.957 (CI 95%: 79.9%-95.3%) for pleural effusions. Conclusion: CT has a low sensitivity and a high specificity for the prediction of diaphragm metastases in ovarian cancer. The size, location, and number of diaphragm lesions do not significantly improve CT detection rat

Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea

Prior studies have reported high response rates with recombinant interferon-a (rIFN-a) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-a,we investigated the outcomes of pegylated-rIFN-a2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PVwho were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 monthswere 69.2%(43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P 5 .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was 26% (range, 284%to 47%) in patients achieving a CR vs 14%(range, 218% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU

Synergistic combination of cytotoxic chemotherapy and cyclin-dependent kinase 4/6 inhibitors in biliary tract cancers

Background and aims: Biliary tract cancers (BTCs) are uncommon, but highly lethal, gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care systemic therapy, but has a modest impact on survival and harbors toxicities, including myelosuppression, nephropathy, neuropathy, and ototoxicity. Whereas BTCs are characterized by aberrations activating the cyclinD1/cyclin-dependent kinase (CDK)4/6/CDK inhibitor 2a/retinoblastoma pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident preclinical efficacy, and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the antitumor efficacy of CDK4/6 inhibitors by the combination with chemotherapy regimens, but their mechanism of action remains elusive.Approach and results: Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity, and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy attributable to autophagy-induced resistance. Notably, triplet therapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated ribonucleotide reductase catalytic subunit M1 reduction, resulting in sensitization to gemcitabine.Conclusions: As such, these data provide robust preclinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.</p

The role of sexuality symptoms in myeloproliferative neoplasm symptom burden and quality of life: An analysis by the MPN QOL International Study Group

BACKGROUND Patients with myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and myelofibrosis, are faced with oppressive symptom profiles that compromise daily functioning and quality of life. Among these symptoms, sexuality-related symptoms have emerged as particularly prominent and largely unaddressed. In the current study, the authors evaluated how sexuality symptoms from MPN relate to other patient characteristics, disease features, treatments, and symptoms. METHODS A total of 1971 patients with MPN (827 with essential thrombocythemia, 682 with polycythemia vera, 456 with myelofibrosis, and 6 classified as other) were prospectively evaluated and patient responses to the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ C30) were collected, along with information regarding individual disease characteristics and laboratory data. Sexuality scores were compared with an age-matched, healthy control population. RESULTS Overall, patients with MPN were found to have greater sexual dysfunction compared with the healthy population (MPN-SAF score of 3.6 vs 2.0; P65 years and in those with cytopenias and transfusion requirements, and those receiving certain therapies such as immunomodulators or steroids. Conclusions The results of the current study identify the topic of sexuality as a prominent issue for the MPN population, and this area would appear to benefit from additional investigation and management

Novel Approach for the Assembly of Highly Efficient SERS Substrates

International audienceIn this paper we present the properties of surface-enhanced Raman scattering (SERS) active substrates elaborated by a low-cost approach. Our methodology relying on capillary assembly and soft lithography allows us to generate periodic two-dimensional (2D) matrixes of 100 nm gold nanoparticle patterns in a very precise, cost-efficient, and large-scale manner. For this study, we assembled nanoparticle aggregates of different sizes (one to six particles) in order to determine the influence of the aggregation on the local electric field enhancement. We further demonstrate that this substrate is greatly efficient not only for SERS but also in metal-enhanced fluorescence (MEF) for local enhancement of conventional fluorescence

Assessment of clinical outcomes with immune checkpoint inhibitor therapy in melanoma patients with CDKN2A and TP53 pathogenic mutations.

BACKGROUND:CDKN2A and TP53 mutations are recurrent events in melanoma, occurring in 13.3% and 15.1% of cases respectively and are associated with poorer outcomes. It is unclear what effect CDKN2A and TP53 mutations have on the clinical outcomes of patients treated with checkpoint inhibitors. METHODS:All patients with cutaneous melanoma or melanoma of unknown primary who received checkpoint inhibitor therapy and underwent genomic profiling with the 50-gene Mayo Clinic solid tumor targeted cancer gene panel were included. Patients were stratified according to the presence or absence of mutations in BRAF, NRAS, CDKN2A, and TP53. Patients without mutations in any of these genes were termed quadruple wild type (QuadWT). Clinical outcomes including median time to progression (TTP), median overall survival (OS), 6-month and 12-month OS, 6-month and 12-month without progression, ORR and disease control rate (DCR) were analyzed according to the mutational status of CDKN2A, TP53 and QuadWT. RESULTS:A total of 102 patients were included in this study of which 14 had mutations of CDKN2A (CDKN2Amut), 21 had TP53 mutations (TP53mut), and 12 were QuadWT. TP53mut, CDKN2Amut and QuadWT mutational status did not impact clinical outcomes including median TTP, median OS, 6-month and 12-month OS, 6-month and 12-month without progression, ORR and DCR. There was a trend towards improved median TTP and DCR in CDKN2Amut cohort and a trend towards worsened median TTP in the QuadWT cohort. CONCLUSION:Cell cycle regulators such as TP53 and CDKN2A do not appear to significantly alter clinical outcomes when immune checkpoint inhibitors are used