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Axminster Town AFC Group

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Asia The Platinum Collection 198

Titanium has long been considered a premium option, with many brands offering titanium watches nowadays, but it wasn't always this way.In fact, titanium is, relatively speaking, new for the watch industry compared to materials such as gold, platinum and steel. While the benefits of titanium are well-known, the material only received widespread attention in the 1960's during the early days of the space race. At the time, research had gained momentum for its use as a construction material for the spacecrafts of the Apollo program due to its lightweight and rust-resistant properties.

Asia The Platinum Collection 198

PIK3R1 encodes the regulatory subunit of PI3K (p85α). Some studies have reported that p85α positively regulates PI3K signaling in CDDP resistance. Because the PI3K pathway is a critical player in tumorigenesis and the ubiquitously hyperactivated signaling pathway in neoplasms, its inhibition both pharmacologically and genetically is considered to be the most promising strategy for targeted cancer treatment [38]. The PI3K pathway has been revealed as a mediator of platinum resistance [39, 40] For instance, AKT activation mediated resistance to caspase-independent CDDP-induced apoptosis through inhibiting the apoptosis-inducing factor-associated pathway [40]. One study reported that PI3K/AKT activation induced the upregulation of BRCA1 in tamoxifen-resistant breast cancer cells and resensitized them to CDDP treatment [23]. Nevertheless, the underlying mechanism of how PIK3R1 mediates resistance to chemotherapy and whether this involves canonical PI3K signaling and downstream BRCA1 activity remains to be investigated in GC.

Both cisplatin and carboplatin crosslink DNA through several mechanisms and interfere with mitosis. Data suggest that cisplatin may have a modest efficacy advantage over carboplatin in the treatment of NSCLC.8 However, the toxicity of cisplatin may be intolerable for many patients, particularly in the palliative setting, where quality of life is paramount. Compared with carboplatin, cisplatin is associated with a greater risk and degree of nausea, alopecia, renal toxicity, ototoxicity, and peripheral neuropathy. Carboplatin is more myelosuppressive, but given the superior tolerability, it has now become the more commonly used platinum compound for the treatment of advanced NSCLC in the United States.

Selection of the specific platinum doublet remains discretionary because the data would suggest similar clinical benefit among the regimens but different toxicity profiles. The Eastern Cooperative Oncology Group (ECOG) 1594 study confirmed equivalent efficacy among four different platinum doublets.9 In this seminal clinical trial, 1207 patients with advanced NSCLC were prospectively randomized to receive one of four platinum doublet chemotherapy regimens: cisplatin plus paclitaxel or docetaxel (taxanes that induce a mitotic block by stabilizing microtubules); cisplatin plus gemcitabine (a nucleotide analog that inhibits essential enzymes for DNA synthesis and function); or carboplatin plus paclitaxel. Patients in all four treatment arms continued therapy until disease progression or intolerable toxicity. Median OS for all enrolled patients was 8.0 months and did not differ statistically among the treatment arms. Similarly, 1- and 2-year survival rates were 34% and 12%, respectively, and did not vary significantly by treatment arm. Patients treated on the carboplatin plus paclitaxel arm experienced less toxicity compared with the patients who received cisplatin-based therapy. Patients with a poor performance status tolerated treatment poorly and had a lower median OS (3.9 months) when compared with patients with a good performance status (7.1 to 10.8 months) regardless of the treatment arm, underscoring the importance of assessing performance status prior to initiation of therapy.

Non-platinum-containing regimens such as gemcitabine plus a taxane or vinorelbine (a vinca alkaloid that inhibits mitosis) have also been studied as first-line treatment of stage IV NSCLC.10,11 However, there was no major advantage in the adverse event profile of non-platinum regimens for them to be favored over the use of platinum-based combinations. For selected patients who are unlikely to tolerate platinum-based therapy, the non-platinum regimens are acceptable therapeutic alternatives.

Other studies have evaluated a switch maintenance strategy. The JMEN trial enrolled 663 patients with advanced NSCLC whose disease had not progressed after four cycles of a non-pemetrexed-containing platinum doublet, and they were randomized to receive immediate pemetrexed therapy (given until progression) or placebo.21 Treatment with maintenance pemetrexed resulted in statistically significant improvements in both median PFS (4.3 versus 2.6 months) and OS (13.4 versus 10.6 months) compared with patients receiving placebo, with manageable toxicity. Among the 481 patients with nonsquamous histology, median OS from the time of randomization was 15.5 months with maintenance pemetrexed versus 10.3 months for patients who received placebo.

The use of targeted agents may also be an effective switch maintenance strategy. In the SATURN trial, 889 patients with advanced NSCLC who did not progress after four cycles of platinum-based chemotherapy were randomized to receive placebo or immediate erlotinib (Tarceva, an orally administered EGFR tyrosine kinase inhibitor (TKI) that blocks tumor signal transduction).23,24 From the time of randomization, a modest improvement in both median PFS (2.8 versus 2.6 months) and median OS (12 versus 11 months) were demonstrated in the group treated with erlotinib. Rash and diarrhea were the main toxicities but were manageable and rarely led to discontinuation of treatment.

Docetaxel was the first chemotherapy approved for second-line therapy; side effects of this agent when given as monotherapy typically include cytopenias, fatigue, fluid retention, and nail changes. Two randomized controlled phase 3 trials have evaluated the efficacy of docetaxel in patients with advanced NSCLC who had progressed after prior chemotherapy.25,33 In a study reported by Shepherd et al,25 204 patients who had been previously treated with a platinum-based regimen were randomized to receive docetaxel or best supportive care. Patients who received docetaxel had a response rate of 5.5% and demonstrated a significant improvement in both median survival (7.5 versus 4.6 months) and 1-year survival (37% versus 19%) compared with those assigned to best supportive care. Two separate reports evaluated the quality of life of patients on these randomized trials.34,35 Both reports demonstrated a statistically significant trend favoring the docetaxel arm, with patients reporting less pain, fatigue, and better overall quality of life when compared with patients on the control arm.

Five randomized phase 3 studies have evaluated first-line treatment with an EGFR-TKI versus standard chemotherapy in patients with EGFR mutation-positive NSCLC.41,42,43,44,45 The initial use of an EGFR-TKI improved PFS from 4.5 to 7 months to 9 to 13 months compared with platinum-based chemotherapy. Median OS was similar between the treatment arms again due to crossover effect and was in the 20- to 30-month range. It is rapidly becoming standard practice to test advanced NSCLC for an EGFR-activating mutation at the initial diagnosis. Presently, reverse transcriptase-polymerase chain reaction (RT-PCR) is required to identify EGFR mutations, an analysis that requires ample tumor DNA for an accurate assessment.

KRAS mutant lung cancer may confer a poorer prognosis compared with other NSCLCs, and data suggest these tumors demonstrate increased resistance to both platinum-based chemotherapy and EGFR-TKIs.48,49 Approximately 15 to 30% of lung adenocarcinomas harbor a KRAS mutation, but unlike EGFR and ALK, KRAS mutations have been difficult to target therapeutically. Recently, the approach of targeting MEK (which is a downstream effector protein in the cell signaling pathway) has shown promise as a therapeutic option. In a randomized phase 2 study, 87 relapsed patients with KRAS mutation-positive NSCLC were treated with standard docetaxel or docetaxel plus the MEK inhibitor selumetinib.50 No responses were seen with docetaxel alone versus a 37% response rate with the addition of selumetinib. A statistically significant improvement in median PFS was identified (2.1 months versus 5.3 months; p = 0.014) in addition to a trend toward improvement in median OS (5.2 months versus 9.4 months; p = 0.21).

Methods: In this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection. The primary end points were event-free survival and pathological complete response (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. Overall survival was a key secondary end point. Safety was assessed in all treated patients.

At the 58th Grammy Awards in 2016, 1989 won Album of the Year and Best Pop Vocal Album, making Swift the first female solo artist to win Album of the Year twice. In the US, 1989 spent 11 weeks atop the Billboard 200 and was certified ninefold platinum the Recording Industry Association of America (RIAA). It also earned multi-platinum certifications in Australia, Canada, and the UK, and has sold over 10 million copies worldwide. Retrospective commentaries regard 1989 as a key success in transforming Swift's image to that of a pop icon, promoting poptimism, but also highlighted how her artistic integrity and public image suffered from increasing media scrutiny.

To ensure a smooth transition to pop, Swift recruited Max Martin and Shellback as major collabo


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