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We present results from end-to-end simulations of observations designed to constrain the rate of change in the expansion history of the Universe using the redshift drift of the Lyman-$\alpha$ forest absorption lines along the lines-of-sight toward bright quasars. For our simulations we take Lyman-$\alpha$ forest lines extracted from Keck/HIRES spectra of bright quasars at $z>3$, and compare the results from these real quasar spectra with mock spectra generated via Monte Carlo realizations. We use the results of these simulations to assess the potential for a dedicated observatory to detect redshift drift, and quantify the telescope and spectrograph requirements for these observations. Relative to Liske et al. (2008), two main refinements in the current work are inclusion of quasars from more recent catalogs and consideration of a realistic observing strategy for a dedicated redshift drift experiment that maximizes $\dot{v}/\sigma_{\dot{v}}$. We find that using a dedicated facility and our designed observing plan, the redshift drift can be detected at $3\sigma$ significance in 15 years with a 25m telescope, given a spectrograph with long term stability with $R=50,000$ and 25% total system efficiency. To achieve this significance, the optimal number of targets is four quasars, with observing time weighted based upon $\dot{v}/\sigma_{\dot{v}}$ and object visibility. This optimized strategy leads to a 9% decrease in the telescope diameter or a 6% decrease in the required time to achieve the same S/N as for the idealized case of uniformly distributing time to the same quasars., Comment: 13 pages, 12 figures, accepted for publication in MNRAS

Kaplan-Meier Survival Curves for Biomarker Substudy (n=33)

KOSMOS is a low-resolution, long-slit, optical spectrograph that has been upgraded at the University of Washington for its move from Kitt Peak National Observatory's Mayall 4m telescope to the Apache Point Observatory's ARC 3.5m telescope. One of the additions to KOSMOS is a slitviewer, which requires the fabrication of reflective slits, as KOSMOS previously used matte slits machined via wire EDM. We explore a novel method of slit fabrication using nanofabrication methods and compare the slit edge roughness, width uniformity, and the resulting scattering of the new fabricated slits to the original slits. We find the kerf surface of the chemically-etched reflective silicon slits are generally smoother than the machined matte slits, with an upper limit average roughness of 0.42 $\pm$ 0.03 $\mu$m versus 1.06 $\pm$ 0.04 $\mu$m respectively. The etched slits have width standard deviations of 6 $\pm$ 3 $\mu$m versus 10 $\pm$ 6 $\mu$m, respectively. The scattering for the chemically-etched slits is higher than that of the machined slits, showing that the reflectivity is the major contributor to scattering, not the roughness. This scattering, however, can be effectively reduced to zero with proper background subtraction. As slit widths increase, scattering increases for both types of slits, as expected. Future work will consist of testing and comparing the throughput and spectrophotometric data quality of these nanofabricated slits to the machined slits with on-sky data, in addition to making the etched slits more robust against breakage and finalizing the slit manufacturing process., Comment: 36 pages, 12 figures, accepted by SPIE

Background Salvage systemic therapy has become the new standard of care in patients with advanced gastric and oesophago-gastric junction (OGJ) adenocarcinoma, following disease progression on first-line fluoropyrimidine and platinum-containing chemotherapy. Pharmacological agents proven to be effective in this setting include both chemotherapy and biological therapy, however, the consensus on the best salvage systemic therapy has not been reached. Objectives To assess the effects of systemic chemotherapy and biological therapy, either alone or in combination, on overall survival (OS) and progression-free survival (PFS) in patients with advanced gastric and OGJ adenocarcinoma, whose disease has progressed on, or relapsed after first-line fluoropyrimidine and platinum-containing chemotherapy. Adverse events (AEs), tumour response rate (TRR) and quality of life (QoL) associated with systemic chemotherapy and/or biological therapy were additionally assessed. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, trial registries and proceedings of the major oncology conferences up to October 2020. We additionally handsearched the reference lists of studies. No language restriction was applied. Selection criteria We included randomised controlled trials (RCTs) comparing salvage systemic therapy (chemotherapy and/or biological therapy) and either another type of salvage systemic therapy, placebo, best supportive care (BSC) or no treatment in patients with gastric and OGJ adenocarcinoma refractory to first-line fluoropyrimidine and platinum-containing chemotherapy. Data collection and analysis Two review authors independently performed selection of eligible studies and the primary author extracted study characteristics and outcome data from included studies. We assessed the quality and risk of bias of eligible studies according to the Cochrane Handbook for Systematic Reviews of Interventions. We expressed pooled estimates of effect using hazard ratio (HR) calculated using an inverse variance random-effects model for time-to-event data, and risk ratio (RR) calculated using Mantel-Haenszel random-effects model for binary data. The certainty of evidence was graded using GRADEpro. Main results We identified 17 RCTs with 5110 participants for inclusion in this review. Tweenty-nine studies are ongoing and twenty studies are awaiting classification. No studies examined the following comparisons: chemotherapy combined with biological therapy versus placebo, BSC or no treatment, chemotherapy combined with biological therapy versus biological therapy, biological therapy versus biological therapy and chemotherapy combined with biological therapy versus chemotherapy combined with biological therapy. Chemotherapy versus placebo, best supportive care or no treatment Chemotherapy probably improves OS (HR = 0.66, 95% CI 0.52 to 0.83, moderate-certainty evidence) based on two studies involving 547 participants and improves PFS (HR = 0.57, 95% CI 0.47 to 0.69, high-certainty evidence) based on one study involving 507 participants over placebo and BSC. Chemotherapy probably increases serious AEs (SAEs) (RR = 1.38, 95% CI 1.20 to 1.59, moderate-certainty evidence) based on one study involving 503 participants. Biological therapy versus placebo, best supportive care or no treatment Biological therapy improves OS (HR = 0.55, 95% CI 0.41 to 0.73, high-certainty evidence) and probably improves PFS (HR = 0.33, 95% CI 0.19 to 0.57, moderate-certainty evidence) over placebo based on three studies involving 781 participants. There is currently insufficient evidence for increased SAEs from biological therapy (RR = 1.14, 95% CI 0.95 to 1.37, low-certainty evidence) based on two studies involving 638 participants. Chemotherapy versus biological therapy This comparison only considered immunotherapy. There is probably no evidence of a difference for OS (HR = 0.82, 95% CI 0.66 to 1.02, moderate-certainty evidence) between chemotherapy and immunotherapy, and immunotherapy probably reduces PFS (HR = 1.27, 95% CI 1.03 to 1.57, moderate-certainty evidence) based on one study involving 395 participants. SAEs may be less frequent with immunotherapy compared to chemotherapy (RR = 0.41, 95% CI 0.30 to 0.57, low-certainty evidence). Chemotherapy combined with biological therapy versus chemotherapy Addition of biological therapy to chemotherapy probably does not improve OS (HR = 0.93, 95% CI 0.83 to 1.04, moderate-certainty evidence) and we are uncertain whether it improves PFS (HR = 0.87, 95% CI 0.74 to 1.02, very low-certainty evidence) based on seven studies involving 2743 participants. We are similarly uncertain whether combined chemotherapy and biological therapy increases SAEs (RR = 1.17, 95% CI 0.95 to 1.44, very low-certainty evidence) based on four studies involving 1618 participants. Chemotherapy versus chemotherapy There is no evidence of a difference for OS and PFS between irinotecan and paclitaxel (HR = 1.13, 95% CI 0.86 to 1.48, low-certainty evidence for OS; HR = 1.14, 95% CI 0.88 to 1.48, low-certainty evidence for PFS) based on one study involving 219 participants. Similarly, there is no evidence to indicate improved OS and PFS from addition of another chemotherapy to docetaxel (HR = 1.05, 95% CI 0.72 to 1.54, low-certainty evidence for OS; HR = 0.75, 95% CI 0.52 to 1.09, low-certainty evidence for PFS) based on two studies involving 121 participants. Grade ≥ 3 neutropenia occurred commonly with both mono- and poly-chemotherapy except for docetaxel-S1 and EOX chemotherapy. Authors' conclusions Survival outcome of patients with advanced gastric and OGJ adenocarcinoma whose disease progressed on first-line fluoropyrimidine and platinum-containing chemotherapy can be improved by chemotherapy and biological therapy. Biological therapy, in particular, achieves this without clear increase in SAEs or QoL impairment. Whether biological therapy is preferred over chemotherapy is still unclear and there is no evidence of a difference for OS outcome, although immunotherapy may be associated with less SAEs. Addition of biological therapy to chemotherapy and poly-chemotherapy are associated with frequent treatment-related toxicity without clear survival benefit.

Synovial metastasis is an unusual entity in solid tumours and only a few cases have been reported in the literature. We report a case of synovial metastasis of the knee in a young patient with progressive rectal adenocarcinoma and review previously published case reports of synovial involvement in advanced colorectal carcinomas. Synovial metastasis is just one of the multiple possibilities of differential diagnosis in patients with cancer suffering from monarthritis. Radiological tests (plain radiographs, bone scans, MRI of the joint and so forth) can be unspecific and cytological examination of the synovial fluid and/or histology of synovial biopsies is essential for a definitive diagnosis so as to tailor the best treatment for patients. Given the poor prognosis associated with these intra-articular secondaries, treatment is often limited to palliation.

Background Patient information leaflets (PILs) are widely utilised within publically funded sexual health clinics to deliver sexual health-related information (SHRI); however, their continued value to clients in the era of social media is unclear. This study aimed to evaluate clients’ opinions on three newly developed PILs and examine client views on other forms of SHRI delivery. Methods: An anonymous self-administered questionnaire was completed by clients attending the Western Sydney Sexual Health Centre (WSSHC) in 2012. High-risk population (HRP) vs non-high-risk population (non-HRP) views on PILs vs alternative methods of SHRI delivery were analysed by using Mann–Whitney U, Wilcoxon, McNemar and χ2 tests. Results: Over half (210/315; (67%)) of the consecutive clients from a culturally diverse population completed the survey. Sex workers (SW) and young people (YP) were significantly likely to have a high school education than non-HRP (P

The average age at diagnosis for colorectal cancer (CRC) in Australia is 69, and the age-specific incidence rises rapidly after age 50 years. The incidence has stabilized or is declining in older age groups in Australia during recent decades, possibly related to the increased uptake of screening and high-risk surveillance. In the same time frame, a rising incidence of CRC in younger adults has been well-documented in the United States. This rise in incidence in the young has not been reported from other countries that share long-term exposure to westernised urban lifestyles. Using data from the Australian Institute of Health and Welfare, we examined trends in national incidence rates for CRC under age 50 years and observed that rates in people under age 40 years have been rising for the last two decades. We further performed a review of the literature regarding CRC in young adults to outline the extent of current understanding, explore potential risk factors such as obesity, alcohol, and sedentary lifestyles, and to identify the questions remaining to be addressed. Although absolute numbers might not justify a population screening approach, the dispersal of young adults with CRC across the primary health-care system decreases probability of their recognition. Patient and physician awareness, aided by stool and emerging blood-screening tests and risk profiling tools, have the potential to aid in identification of those young adults who would most benefit from a colonoscopy through early detection of CRCs or by removal of advanced polyps.

To evaluate the efficacy and tolerability of lapatinib (L) and intravenous vinorelbine (V) in patients with metastatic HER2-positive breast cancer who have previously received two lines of anti-HER2 therapy (i.e. trastuzumab [T] with chemotherapy and lapatinib with capecitabine [LC]).Consenting patients with measurable or evaluable disease and normal cardiac function who had progressed were recruited. Patients received LV (lapatinib 1250 mg orally daily, vinorelbine 20 mg/m(2) intravenously on days 1 and 8 every 3 weeks) until progressive disease, intolerable toxicity or patient request.The trial was closed early following inclusion of 19 patients due to slow accrual. Ten, five and four patients had received two, three and more than four lines of chemotherapy with T and LC, respectively, prior to study entry. Patients received a median of 5 cycles (range 1-18) of LV. Confirmed partial response was seen in 2 of 16 patients with measurable disease (12.5%); stable disease 24 weeks was seen in two patients (10.5%) with a clinical benefit rate of 20%. Fatigue and any grade neutropenia occurred commonly, but grade 4 severity occurred in only 5 and 11%, respectively. There were no episodes of cardiac dysfunction and no treatment-related deaths. The median progression-free survival was 3.9 months and overall survival (OS) was 9.1 months.The combination of LV demonstrated modest efficacy but was well tolerated. This combination may be of benefit to those patients who are unable to access the newer anti-HER2 agents and the low rate of treatment-emergent adverse effects will enable patients' symptoms, such as pain, to be minimized.

Evidence supporting improved outcomes for small cell lung cancer (SCLC) in recent decades is limited. This study aimed to identify patterns of care and survival over two time periods; 1 January 1987 to 31 December 1996 (cohort A) and 1 January 1997 to 31 December 2006 9 (cohort B).Patients' characteristics, management and outcome data were extracted from the Hospital Cancer Registry and clinical records. Survival analysis was determined using the Kaplan-Meier method and the log-rank test. Factors influencing survival outcome were assessed using Cox proportional hazards regression.The total number of patients was 392 (224 in cohort A, 168 in cohort B). Overall 38% patients in cohort A and 24% in cohort B had limited stage (LS) disease at diagnosis. Combined chemoradiotherapy for LS increased from 5% in cohort A to 65% in cohort B. Overall 19% of patients in cohort A and 24% in cohort B received symptomatic treatment alone (STA). Median survival for LS in cohort B was significantly higher (19.5 months), than in cohort A (11.8 months) (P = 0.03). In extensive stage (ES) disease, median survival was 6.2 months in cohort A and 4.3 months in cohort B (P = 0.7). Variables for poorer outcome were STA, male gender, poor performance status, ES and whether the diagnosis was made in the earlier time period in cohort A.Outcomes for LS SCLC have improved with combined chemoradiotherapy, in keeping with worldwide data. The trends may also reflect recent improvements in staging and standardization of treatment. The outcome for ES-SCLC remains poor.

Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of the 20S proteasome. NPI-0052 has a novel structure leading to a unique proteasome inhibition, toxicology and effect profile. Preclinical research suggests an improved therapeutic ratio and activity in hematologic and solid tumor malignancy models. Secondary to these findings, clinical trials are being conducted in patients with myeloma, lymphomas, leukemias and solid tumors. Materials and Methods: In this study patients with solid tumor, lymphoma or leukemia diagnoses were treated with NPI-0052 administered weekly, for 3 weeks in 4-week cycles in a 3+3 design dose escalation. The dose of NPI-0052 was escalated in 50–100% increments dependent on observed adverse events (AE). In addition to regular safety monitoring, proteasome inhibition (PI) (baseline, D1 & D15) and pharmacokinetics PK (D1 & D15) were assayed in blood. Once a Recommended Phase 2 Dose (RP2D) is identified, RP2D cohorts of 10 patients in each lymphoma and CLL are enrolled. Results: 25 patients have been treated at doses ranging from 0.1 mg/m2 to 0.7 mg/m2. The AE profile has been very tolerable with fatigue, transient peri-infusion site discomfort and lymphopenia being commonly ascribed to NPI-0052. Whole blood pharmacokinetics were calculated for all patients on study. At the highest dose assessed PK parameters were (mean ± SD) AUCtot =215±129 ng/mL*min; Cmax =22.8 ±14 ng/mL; t1/2 =13.5 ± 9.2 mins; clearance= 7.8 ± 8.2 L/min and Vss = 132 ± 192 L. AUC and Cmax increased linearly with dose and the kinetics are apparently not dose dependant. PI has been assayed in blood, indicating a dose:response relationship with inhibition of chymotrypsin-like activity up to 100% observed and mean Day 1 inhibition of 78%. This level of proteasome inhibition is higher than that reported with standard doses of bortezomib, yet the profile of adverse drug reactions associated with bortezomib has not been observed. A total of 7 patients (33%) have had stable disease for at least 2 cycles (8 weeks; 2months), including one each with mantle cell lymphoma (4 cycles), Hodgkin’s lymphoma (4 cycles), follicular lymphoma (4 cycles) and sarcoma (5 cycles) and prostate adenocarcinoma, and two with melanoma (4 cycles). Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the predicted efficacious range while producing a toxicity profile that is tolerable and dissimilar to that of the standard of care proteasome inhibitor bortezomib. These data have supported additional studies being initiated in hematologic malignancies and solid tumors.