Study of helium transfer technology for STICCR: Fluid management

The Space Infrared Telescope Facility (SIRTF) is a long life cryogenically cooled space based telescope for infrared astronomy from 2 to 700 microns currently under study and planned for launch in the mid 90's. SIRTF will operate as a multi-user facility, initially carrying 3 instruments at the focal plane. It will be cooled to below 2 K by superfluid liquid helium to achieve radiometric sensitivity limited only by the statistical fluctuations in the natural infrared background radiation over most of its spectral range. The lifetime of the mission will be limited by the lifetime of the liquid helium supply, and is currently baselined to be 2 years. Candidates are reviewed for a liquid management device to be used in the resupply of liquid helium, and for the selection of an appropriate candidate

Metastatic Renal Cell Carcinoma Rapidly Progressive to Sunitinib: What to Do Next?

Background: From 10% to 26% of patients with metastatic renal cell carcinoma (mRCC) experience rapidly progressive disease (PD) on treatment with sunitinib. Objective: To investigate the benefit of subsequent treatment with another tyrosine kinase inhibitor (TKI) or a mammalian target of rapamycin (mTOR) inhibitor in such primary refractory patients. Design, setting, and participants: A total of 150 mRCC patients with rapidly PD on first- line sunitinib (within two cycles, n = 93, or four cycles, n = 57) were identified: median age 59 yr; nephrectomy 86%; histological subtypes: clear cell (77.8%), papillary (14%), and sarco- matoid features (18%); according to the Memorial Sloan-Kettering Cancer Center and French classifications: good risk (11% and 7%, respectively), intermediate (68% and 63%, respectively), and poor (21% and 29%, respectively). Outcome measurements and statistical analysis: Data were retrospectively collected by a questionnaire from 19 European oncology centers between March 2005 and March 2011. Pro- gression-free survival (PFS) and overall survival (OS) were calculated (Kaplan-Meier method). Results and limitations: Median OS from the start of first-line treatment was 7.4 mo. Second-line treatment was administered to 86 (57%) patients (44 mTOR inhibitors: 23 ever- olimus and 21 temsirolimus; 39 TKIs alone or in combination; three chemotherapy). Second- line PFS was not significantly different between TKIs and mTOR inhibitors (2.0 vs 0.9 mo; p = 0.536). Median OS from the start of second-line treatment was 5.0 mo for mTOR inhibitors and 6.6 mo for TKIs (p = 0.15). Conclusions: Treatment with further TKIs or mTOR inhibitors for mRCC patients primarily refractory to first-line sunitinib in the observed time period achieved very minimal benefit, suggesting avoiding TKI rechallenge and possibly preferring alternative strategies, such as immune checkpoint inhibitors, after PD to a treatment line including a TKI in this setting. Patient summary: The present work collected data about 150 patients affected by meta- static renal cell carcinoma, who received one of the current standard of care as first-line treatment, namely, the antiangiogenic drug sunitinib, and experienced rapid worsening of the disease. We investigated and described the subsequent outcome of such patients treated with two different types of drug, administered as second-line therapy, to better understand the best strategy to adopt for patients who got no benefit from sunitinib and to describe the current therapeutic approach in such cases

Computational modeling of ovarian cancer dynamics suggests optimal strategies for therapy and screening

High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Treatment is not uniform, with some patients undergoing primary debulking surgery followed by chemotherapy (PDS) and others being treated directly with chemotherapy and only having surgery after three to four cycles (NACT). Which strategy is optimal remains controversial. We developed a mathematical framework that simulates hierarchical or stochastic models of tumor initiation and reproduces the clinical course of HGSC. After estimating parameter values, we infer that most patients harbor chemoresistant HGSC cells at diagnosis and that, if the tumor burden is not too large and complete debulking can be achieved, PDS is superior to NACT due to better depletion of resistant cells. We further predict that earlier diagnosis of primary HGSC, followed by complete debulking, could improve survival, but its benefit in relapsed patients is likely to be limited. These predictions are supported by primary clinical data from multiple cohorts. Our results have clear implications for these key issues in HGSC management

Long-term responders on olaparib maintenance in high-grade serous ovarian cancer: Clinical and molecular characterization

Purpose: Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboring BRCA1/2 mutations. The objective of this study was to characterize long-term (LT) versus short-term (ST) responders to olaparib. Experimental Design: A comparative molecular analysis of Study 19 (NCT00753545), a randomized phase II trial assessing olaparib maintenance after response to platinum-based chemotherapy in HGSOC, was conducted. LT response was defined as response to olaparib/placebo > 2 years, ST as < 3 months. Molecular analyses included germline BRCA1/2 status, three-biomarker homologous recombination deficiency (HRD) score, BRCA1 methylation, and mutational profiling. Another olaparib maintenance study (Study 41; NCT01081951) was used as an additional cohort. Results: Thirty-seven LT (32 olaparib) and 61 ST (21 olaparib) patients were identified. Treatment was significantly associated with outcome (P < 0.0001), with more LT patients on olaparib (60.4%) than placebo (11.1%). LT sensitivity to olaparib correlated with complete response to chemotherapy (P < 0.05). In the olaparib LT group, 244 genetic alterations were detected, with TP53, BRCA1, and BRCA2 mutations being most common (90%, 25%, and 35%, respectively). BRCA2 mutations were enriched among the LT responders. BRCA methylation was not associated with response duration. High myriad HRD score (>42) and/or BRCA1/2 mutation was associated with LT response to olaparib. Study 41 confirmed the correlation of LT response with olaparib and BRCA1/2 mutation. Conclusions: Findings show that LT response to olaparib may be multifactorial and related to homologous recombination repair deficiency, particularly BRCA1/2 defects. The type of BRCA1/2 mutation warrants further investigation. (C) 2017 AACR

Epithelial Ovarian Cancer

Epithelial ovarian cancer generally presents at an advanced stage and is the most common cause of gynaecological cancer death. Treatment requires expert multidisciplinary care. Population-based screening has been ineffective, but new approaches for early diagnosis and prevention that leverage molecular genomics are in development. Initial therapy includes surgery and adjuvant therapy. Epithelial ovarian cancer is composed of distinct histological subtypes with unique genomic characteristics, which are improving the precision and effectiveness of therapy, allowing discovery of predictors of response such as mutations in breast cancer susceptibility genes BRCA1 and BRCA2, and homologous recombination deficiency for DNA damage response pathway inhibitors or resistance (cyclin E1). Rapidly evolving techniques to measure genomic changes in tumour and blood allow for assessment of sensitivity and emergence of resistance to therapy, and might be accurate indicators of residual disease. Recurrence is usually incurable, and patient symptom control and quality of life are key considerations at this stage. Treatments for recurrence have to be designed from a patient's perspective and incorporate meaningful measures of benefit. Urgent progress is needed to develop evidence and consensus-based treatment guidelines for each subgroup, and requires close international cooperation in conducting clinical trials through academic research groups such as the Gynecologic Cancer Intergroup.status: publishe

Disclosure of cancer diagnosis and quality of life in cancer patients: should it be the same everywhere?

<p>Abstract</p> <p>Background</p> <p>Evidence suggests that truth telling and honest disclosure of cancer diagnosis could lead to improved outcomes in cancer patients. To examine such findings in Iran, this trial aimed to study the various dimensions of quality of life in patients with gastrointestinal cancer and to compare these variables among those who knew their diagnosis and those who did not.</p> <p>Methods</p> <p>A consecutive sample of patients with gastrointestinal cancer being treated in Cancer Institute in Tehran, Iran was prospectively evaluated. A psychologist interviewed patients using the Iranian version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Patients were categorized into two groups: those who knew their diagnosis and those who did not. Independent sample t-test was used for group comparisons.</p> <p>Results</p> <p>In all 142 patients were interviewed. A significant proportion (52%) of patients did not know their cancer diagnosis and 48% of patients were aware that they had cancer. They were quite similar in most characteristics. The comparison of quality of life between two groups indicated that those knew their diagnosis showed a significant lower degree of physical (P = 0.001), emotional (P = 0.01) and social functioning (P < 0.001), whereas the global quality of life and other functional scales including role functioning and cognitive functioning did not show significant result. There were no statistically significant differences between symptoms scores between two groups, except for fatigue suggesting a higher score in patients who knew their diagnosis (P = 0.01). The financial difficulties were also significantly higher in patients who knew their cancer diagnosis (P = 0.005). Performing analysis of variance while controlling for age, educational status, cancer site, and knowledge of cancer diagnosis, the results showed that the knowledge of cancer diagnosis independently still contributed to the significant differences observed between two groups.</p> <p>Conclusion</p> <p>Contrary to expectation the findings indicated that patients who did not know their cancer diagnosis had a better physical, social and emotional quality of life. It seems that due to cultural differences between countries cancer disclosure guidelines perhaps should be differing.</p

Clinical parameters affecting survival outcomes in patients with low-grade serous ovarian carcinoma: An international multicentre analysis

Background: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC. Methods: We performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan–Meier survival curves. Results: Of the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients’ median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage IV. Of the 377 patients with surgical data, 200 (53.0%) had no visible residual disease. Of the 361 patients with chemotherapy data, 330 (91.4%) received first-line platinum-based chemotherapy. The median follow-up duration was 5.0 years. The median progression-free survival and overall survival were 43.2 months and 110.4 months, respectively. Multivariate analysis indicated a statistically significant impact of stage and residual disease on progression-free survival and overall survival. Platinum-based chemotherapy was not associated with a survival advantage. Conclusion: This multicentre analysis indicates that complete surgical cytoreduction to no visible residual disease has the most impact on improved survival in LGSC. This finding could immediately inform and change practice.publishedVersio

Impact of the putative cancer stem cell markers and growth factor receptor expression on the sensitivity of ovarian cancer cells to treatment with various forms of the HER inhibitors and cytotoxic drugs

Increased expression and activation of human epidermal growth factor receptor (EGFR) and HER-2 have been reported in numerous cancers. The aim of this study was to determine the sensitivity of a large panel of human ovarian cancer cell lines (OCCLs) to treatment with various forms of small molecule tyrosine kinase inhibitors (TKIs) and cytotoxic drugs. The aim was to see if there was any association between the protein expression of various biomarkers including three putative ovarian cancer stem cell (CSC) markers (CD24, CD44, CD117/c-Kit), P-glycoprotein (P-gp), and HER family members and response to treatment with these agents. The sensitivity of 10 ovarian tumour cell lines to the treatment with various forms of HER TKIs (gefitinib, erlotinib, lapatinib, sapitinib, afatinib, canertinib, neratinib), as well as other TKIs (dasatinib, imatinib, NVP-AEW541, crizotinib) and cytotoxic agents (paclitaxel, cisplatin and doxorubicin), as single agents or in combination, was determined by SRB assay. The effect on these agents on the cell cycle distribution, and downstream signaling molecules and tumour migration were determined using flow cytometry, western blotting, and the IncuCyte Clear View cell migration assay respectively. Of the HER inhibitors, the irreversible pan-TKIs (canertinib, neratinib and afatinib) were the most effective TKIs for inhibiting the growth of all ovarian cancer cells, and for blocking the phosphorylation of EGFR, HER-2, AKT and MAPK in SKOV3 cells. Interestingly, while the majority of cancer cells were highly sensitive to treatment with dasatinib, they were relatively resistant to treatment with imatinib (i.e., IC50 >10 µM). Of the cytotoxic agents, paclitaxel was the most effective for inhibiting the growth of OCCLs, and of various combinations of these drugs, only treatment with a combination of NVP-AEW541 and paclitaxel produced a synergistic or additive anti-proliferative effect in all three cell lines examined (i.e., SKOV3, Caov3, ES2). Finally, of the TKIs, only treatment with afatinib, neratinib and dasatinib were able to reduce the migration of HER-2 overexpressing SKOV3 cells. We did not find any significant association between the expression of putative ovarian CSC marker, HER family members, c-MET, ALK, and IGF-IR and the response to the irreversible HER TKIs. Our results support the need for further investigations of the therapeutic potential of these irreversible HER family blockers in ovarian cancer, and the therapeutic potential of dasatinib when used in combination with the inhibitors of the HER family members in ovarian cancer