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Tucatinib is a potent tyrosine kinase inhibitor selective for human epidermal growth factor receptor 2 (HER2) approved by the US Food and Drug Administration for the treatment of HER2‐positive metastatic breast cancer and in development for other HER2‐positive solid tumors. Modest, reversible serum creatinine (SCr) elevations have been observed in tucatinib clinical trials. SCr is conveyed by the renal drug transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) and 2‐K (MATE2‐K) and can increase in the presence of inhibitors of these transporters. In vitro, tucatinib inhibited OCT2‐, MATE1‐, and MATE2‐K‐mediated transport of metformin, with IC50 values of 14.7, 0.340, and 0.135 µM, respectively. Tucatinib also inhibited OCT2‐ and MATE1‐mediated transport of creatinine, with IC50 values of 0.107 and 0.0855 µM, respectively. A phase 1 study with metformin administered orally in the absence and presence of tucatinib was conducted in 18 healthy subjects. Renal function was assessed by measuring glomerular filtration rate (GFR; based on iohexol plasma clearance) and endogenous markers (SCr, cystatin C‐based estimated glomerular filtration rate [eGFR]) with and without tucatinib. Metformin exposure increased (1.4‐fold) and renal clearance decreased (29.99‐17.64 L/h) with tucatinib, with no effect on metformin maximum concentration. Creatinine clearance transiently decreased 23% with tucatinib. GFR and eGFR, which are unaffected by OCT2 and/or MATE1/2‐K transport, were unchanged with tucatinib. These data demonstrate that tucatinib inhibits OCT2‐ and MATE1/2‐K‐mediated tubular secretion of creatinine, which may manifest as mild SCr elevations that are not indicative of renal impairment.

Background Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. Patients and methods This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). Results Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively. Conclusion The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. Clinical Trial Registration NCT01921335.

This article analyses how jihadist ideology groups discursively represent “the West” and “non-believers” in their online propagandamagazines. In doing so, it contributes to the field of Critical Te...

Summary Introduction The phosphotidylinositol-3 kinase (PI3K)/serine–threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC. Methods Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m2 IV every 21 days) with or without PX-866 (8 mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. Results 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P = 0.13). Median PFS was 92 days in Arm A and 82 days in Arm B (P = 0.42). There was no difference in OS between the two arms (263 vs. 195 days; P = 0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed. Conclusion The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.

This manuscript reports on a prospective, randomized study of cetuximab plus/minus a small molecule PI3K inhibitor (PX-866) targeting the protein product of PIK3CA, the gene with the highest rate of activating mutations in head and neck squamous cell cancer (HNSCC). The combination of PX-866 and cetuximab failed to improve outcomes compared with cetuximab alone in patients with advanced HNSCC. Background The phosphotidylinositol-3 kinase (PI3K)/serine–threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. A phase I trial demonstrated tolerability of this combination. This randomized phase II study evaluated PX-866 combined with cetuximab in patients with advanced, refractory HNSCC. Methods Patients with recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1 : 1) to cetuximab with or without PX-866 (8 mg p.o. daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS), toxicity, and correlation of key biomarkers with efficacy outcomes. Results Eighty-three patients were enrolled. There was a similar response rate between arms (10% versus 7%). Of patients for whom tissue was assessable, 57% were human papillomavirus (HPV) positive. Median PFS was 80 days in both arms and there was no difference in OS between the two arms (211 versus 256 days). Overall toxicity was higher in arm A compared with arm B, especially in terms of nausea (53% versus 23%), vomiting (45% versus 15%), fatigue (43% versus 23%), diarrhea (40% versus 21%), and hypokalemia (25% versus 10%). Grade 3 or higher adverse events were infrequent, but more common in the combination arm although without a specific pattern.PIK3CA mutations were observed in 17% of the cases assessed, andPTEN loss was infrequently observed. Conclusion The addition of PX-866 to cetuximab did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC enrolled without molecular preselection. In this contemporary cohort, HPV-positive patients comprised the majority, and neither HPV-positive nor HPV-negative patients derived clinical benefit for the addition of cetuximab plus PX-866.

Background This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and antitumor activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with cetuximab in patients with incurable colorectal cancer or squamous cell carcinoma of the head and neck. Methods PX-866 was administered at escalating doses (6–8 mg daily) combined with cetuximab given at a 400 mg/m2 loading dose followed by 250 mg/m2 weekly. A “3 + 3” study design was used. Prior therapy with anti-EGFR therapies, including cetuximab, was allowed. Results Eleven patients were enrolled. The most frequent treatment-emergent adverse event was diarrhea (90.1 %), followed by hypomagnesemia (72.2 %), vomiting (72.2 %), fatigue (54.5 %), nausea (54.5 %), rash (45.5 %) and peripheral edema (40 %). No dose limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent PX-866 MTD. Best responses in 9 evaluable patients were: 4 partial responses (44.4 %), 4 stable disease (44.4 %), and 1 disease progression (11.1 %). The median progression free survival was 106 days (range: 1–271). Conclusion Treatment with PX-866 and cetuximab was tolerated with signs of anti-tumor activity. Further development of this combination is warranted.

Focusing on a selection of poems written during Allen Ginsberg’s visits to Britain between 1958 and 1979, an attempt is made to show how Ginsberg’s British poetry might productively be read in the context of William Blake’s mythopoetic system, particularly in so far as it relates to the Blakean figures of Albion and Jerusalem. Ginsberg’s poetic vision of a Blakean Albion is revealed to be more complex, and more problematic, than might be supposed. This is partly because Ginsberg’s own position is conflicted; as a key representative of American Beat poetry and later of American counterculture, he is nonetheless engaged in these ‘British’ poems in re-envisioning and reshaping Blake’s Albion. Such nationalist tensions are not, however, restricted to Ginsberg’s work; they can also be linked to similar conflicts between nationalism and internationalism which already exist within Blake’s own vision of Albion.

Background: This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), pharmacokinetics, and antitumour activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with docetaxel in patients with incurable solid tumours. Methods: PX-866 was administered at escalating doses (4–8 mg daily) with docetaxel 75 mg m−2 intravenously every 21 days. Archived tumour tissue was assessed for potential predictive biomarkers. Results: Forty-three patients were enrolled. Most adverse events (AEs) were grade 1 or 2. The most frequent study drug-related AE was diarrhoea (76.7%), with gastrointestinal disorders occurring in 79.1% (docetaxel-related) and 83.7% (PX-866-related). No dose-limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent MTD. Co-administration of PX-866 and docetaxel did not affect either drug's PKs. Best responses in 35 evaluable patients were: 2 partial responses (6%), 22 stable disease (63%), and 11 disease progression (31%). Eleven patients remained on study for >180 days, including 8 who maintained disease control on single-agent PX-866. Overall median progression-free survival (PFS) was 73.5 days (range: 1–569). A non-significant association between longer PFS for PIK3CA-MUT/KRAS-WT vs PIK3CA-WT/KRAS-WT was observed. Conclusion: Treatment with PX-866 and docetaxel was well tolerated, without evidence of overlapping/cumulative toxicity. Further investigation with this combination is justified.

Background Annual influenza vaccination is recommended but not compulsory for healthcare workers in Australia, including medical students. A quarter of healthcare workers are estimated to have an influenza infection in any given year, with a subsequent transmission risk to colleagues and patients. During clinical placements, medical students are also at risk of influenza. While compliance with other vaccination requirements are high, influenza vaccine uptake of healthcare workers and medical students remain low globally. We aimed to explore medical students’ influenza vaccination rates, attitudes, knowledge and intended practices at a large Australian university. Method A 35 item self-administered online survey was distributed to medical students enrolled at a large Australian university (UNSW Australia) in April/May 2014. The survey examined the knowledge, attitudes and practices of medical students towards influenza vaccination and identified factors associated with vaccine uptake. Results Of the 606 students, 53.8% (95%CI 49.8–57.8%) receiving their most recent influenza vaccine in 2014. Self-protection was the most common motivator (83%) and inconvenience (64%) the most common barrier to vaccination, despite access to on campus clinics. Students generally held positive attitudes to the influenza vaccine and vaccination recommendations, though some misconceptions existed. The majority (61%) were in support of mandatory influenza vaccination policies for medical students. Significant predictors of influenza vaccination included living on campus, clinical experience, awareness of vaccination recommendations and agreeing that vaccination was important for medical students, while those with perceived time constraints were less likely to be vaccinated. Conclusion Misconceptions and access to influenza vaccine were barriers to uptake of influenza vaccine by medical students. Medical programs need to emphasise the benefits of influenza vaccination in the protection of healthcare workers and patient safety across the medical education program. Our results suggesting majority support for mandatory influenza vaccination may represent a shifting perspective in the medical community.

Compensator-based IMRT coupled with the high dose rate flattening filter free (FFF) beams offers an intriguing possibility of delivering an intensity modulated radiation field in just a few seconds. As a first step, the authors evaluate the dosimetric accuracy of the treatment planning system (TPS) FFF beam model with compensators.A 6 MV FFF beam from a TrueBeam accelerator (Varian Medical Systems, Palo Alto CA) was modeled in PINNACLE TPS (v. 9.0, Philips Radiation Oncology, Fitchburg WI). Flat brass slabs from 0.3 to 7 cm thick and an 18° brass wedge were used to adjust the beam model. A 2D (MAPCHECK) and 3D (ARCCHECK) diode arrays (Sun Nuclear Corp, Melbourne FL), were investigated for use with the compensator FFF beams. Corrections for diode sensitivity caused by the spectral changes in the beam were introduced. Four compensator plans based on the AAPM TG-119 report were developed. A composite ion chamber measurement, beam by beam MAPCHECK measurements, and a composite ARCCHECK measurement were performed. The array results were analyzed with the same thresholds as in TG-119 report-3%/3 mm with global dose normalization-as well as with the more stringent combinations of the gamma analysis criteria.The FFF beam shows a greater variation of the effective attenuation coefficient with brass thickness due to the prevalence of the low energy photons compared to the conventional 6X beam. As a result, a compromise had to be made while trying to achieve dose agreement for a combination of field sizes, brass thicknesses, and measurement depths (≥5 cm in water). An agreement of measured and calculated dose to within 1% was observed for brass thicknesses up to 2 cm. For the 3 cm slab, an error of up to 2.8% was noted for the field sizes above 10 × 10 cm(2), and up to 3.8% for the 5 × 5 cm(2) field. Both diode arrays exhibit a substantial sensitivity drop as the compensator thickness increases, reaching 10% for a 7 cm brass slab. A simple correction based on the brass thickness along the ray was introduced to counteract this effect. Pooled for five profiles, the average ratio of uncorrected and corrected MAPCHECK to ion chamber readings are 0.966 and 1.008, respectively. With the proper correction, all MAPCHECK measurement to calculation comparisons exhibit 100% γ(3%/3 mm) passing rates with global dose-error normalization. For the TG-119-type plans, the average γ(2%/2 mm) passing rate with local normalization is 94% (range 87.8%-98.3%). The lower ARCCHECK γ-analysis passing rates (corrected for diode sensitivity) are predictable based on the observed PDD discrepancies. However, with the 3%/3 mm thresholds and global normalization, the average γ-analysis passing rate is 96.4% (range 89.9%-100%).MAPCHECK analysis demonstrates high passing rates with the stringent γ(2%/2 mm) and local normalization criteria combination. The geometry of the ARCCHECK array creates a stress test for the FFF TPS model because of the shallow depth of the entrance diodes and large air cavity. Hence, the ARCCHECK γ-analysis passing rates are lower than with the MAPCHECK, while still on par with TG-119.