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\"They are the greatest young heroes this world--or any world--has ever known. They are the Titans. And now, from the void between the worlds, one of their most legendary members has emerged. Wally West, a.k.a. Kid Flash, has returned. Powered by the Speed Force, he's brought the secrets of time and space following in his wake. And with those secrets comes a prize that Deathstroke, the most lethal foe the Titans have ever faced, would do anything to claim: the rebirth of his long-dead son. Now Titans from every team--past, present or future--must unite to stop the killer called Slade from claiming his sinister prize. Can the Titans and the Teen Titans work together to stop this evil? Or will the two teams turn on each other, leaving Deathstroke to seize control?\"-- Provided by publisher.

The use of data from the real world to address clinical and policy-relevant questions that cannot be answered using data from clinical trials is garnering increased interest. Indeed, data from cancer registries and linked treatment records can provide unique insights into patients, treatments and outcomes in routine oncology practice. In this Review, we explore the quality of real-world data (RWD), provide a framework for the use of RWD and draw attention to the methodological pitfalls inherent to using RWD in studies of comparative effectiveness. Randomized controlled trials and RWD remain complementary forms of medical evidence; studies using RWD should not be used as substitutes for clinical trials. The comparison of outcomes between nonrandomized groups of patients who have received different treatments in routine practice remains problematic. Accordingly, comparative effectiveness studies need to be designed and interpreted very carefully. With due diligence, RWD can be used to identify and close gaps in health care, offering the potential for short-term improvement in health-care systems by enabling them to achieve the achievable.In the past few years, the use of data from the real world has garnered increasing interest; however, studies using real-world data (RWD) should not be used as substitutes for clinical trials. The authors of this Review explore the quality of RWD, provide a framework for the use of RWD and draw attention to the methodological pitfalls inherent to using RWD.

During the COVID-19 global pandemic, the cancer community faces many difficult questions. We will first discuss safety considerations for patients with cancer requiring treatment in SARS-CoV-2 endemic areas. We will then discuss a general framework for prioritizing cancer care, emphasizing the precautionary principle in decision making.

AbstractObjectiveTo quantify the association of cancer treatment delay and mortality for each four week increase in delay to inform cancer treatment pathways.DesignSystematic review and meta-analysis.Data sourcesPublished studies in Medline from 1 January 2000 to 10 April 2020.Eligibility criteria for selecting studiesCurative, neoadjuvant, and adjuvant indications for surgery, systemic treatment, or radiotherapy for cancers of the bladder, breast, colon, rectum, lung, cervix, and head and neck were included. The main outcome measure was the hazard ratio for overall survival for each four week delay for each indication. Delay was measured from diagnosis to first treatment, or from the completion of one treatment to the start of the next. The primary analysis only included high validity studies controlling for major prognostic factors. Hazard ratios were assumed to be log linear in relation to overall survival and were converted to an effect for each four week delay. Pooled effects were estimated using DerSimonian and Laird random effect models.ResultsThe review included 34 studies for 17 indications (n=1 272 681 patients). No high validity data were found for five of the radiotherapy indications or for cervical cancer surgery. The association between delay and increased mortality was significant (P<0.05) for 13 of 17 indications. Surgery findings were consistent, with a mortality risk for each four week delay of 1.06-1.08 (eg, colectomy 1.06, 95% confidence interval 1.01 to 1.12; breast surgery 1.08, 1.03 to 1.13). Estimates for systemic treatment varied (hazard ratio range 1.01-1.28). Radiotherapy estimates were for radical radiotherapy for head and neck cancer (hazard ratio 1.09, 95% confidence interval 1.05 to 1.14), adjuvant radiotherapy after breast conserving surgery (0.98, 0.88 to 1.09), and cervix cancer adjuvant radiotherapy (1.23, 1.00 to 1.50). A sensitivity analysis of studies that had been excluded because of lack of information on comorbidities or functional status did not change the findings.ConclusionsCancer treatment delay is a problem in health systems worldwide. The impact of delay on mortality can now be quantified for prioritisation and modelling. Even a four week delay of cancer treatment is associated with increased mortality across surgical, systemic treatment, and radiotherapy indications for seven cancers. Policies focused on minimising system level delays to cancer treatment initiation could improve population level survival outcomes.

Applying a new, more sensitive single-cell transcriptomics method to diagnosis, remission and progression samples from patients with chronic myeloid leukemia reveals insight into the heterogeneity of cells that resist treatment with targeted therapy, as well as into the dynamics of disease progression and its effects on nontransformed hematopoietic stem cells. Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy. Analysis of nonleukemic SCs from patients with CML also provided new insights into cell-extrinsic disruption of hematopoiesis in CML associated with clinical outcome. Furthermore, we used this single-cell approach to identify a blast-crisis-specific SC population, which was also present in a subclone of CML-SCs during the chronic phase in a patient who subsequently developed blast crisis. This approach, which might be broadly applied to any malignancy, illustrates how single-cell analysis can identify subpopulations of therapy-resistant SCs that are not apparent through cell-population analysis.

Many newly approved cancer therapeutics offer limited clinical benefits yet are still prescribed to patients. A common-sense revolution in oncology would prioritize treatments that meaningfully improve survival and quality of life.

[...]the drug nab-paclitaxel (brand name abraxane) costs 50 times more per dose than paclitaxel.7 The proposed benefit of abraxane over paclitaxel is a lesser frequency of neuropathy and probably infusion reactions, but several cancer types are still being treated with paclitaxel as the standard of care and the minor differences in some side-effects do not justify the price difference between paclitaxel and abraxane. In 2016, the NAPOLI-1 trial tested fluorouracil plus nanoliposomal irinotecan versus fluorouracil as second-line treatment in patients who had progressed on gemcitabine-based first-line therapy (but were irinotecan naive).8 Again, nanoliposomal irinotecan is effectively just expensive irinotecan. Since FOLFIRINOX is active in pancreatic cancer, it is understandable that irinotecan would be an active agent in pancreatic cancer. [...]this trial concluded that although there was no statistically significant overall survival benefit observed, “the [hazard ratio] numerically favored olaparib”.11 At the 2023 ASCO Gastrointestinal Cancers Symposium, the results of NAPOLI-3 trial were presented.12 This randomised controlled trial assigned patients with advanced pancreatic cancer to receive first-line NALIRIFOX (nanoliposomal irinotecan, fluorouracil, folinic acid, and oxaliplatin) or gemcitabine plus nab-paclitaxel. [...]if we look at the past 25 years of treatments for metastatic pancreatic cancer, we arrive at a very sobering picture. [...]we shifted towards a normalisation of progression-free survival as the primary endpoint in pancreatic cancer trials

Disease progression is defined by the Response Evaluation Criteria in Solid Tumors as an increase in the sum of maximum tumour diameters of at least 20%, the development of any new lesions, or an unequivocal increase in non-measurable malignant disease.1 These criteria were originally developed to categorise the outcomes of new cancer treatments in phase 2 studies and facilitate the advancement of promising therapies to phase 3 trials. Several studies have shown that delays in progression are not automatically associated with quality-of-life improvements.9 Therefore, even after rephrasing, we need to continue to demand that quality of life is separately assessed and reported in clinical trials, and not simply assume that prolonging the progression-free interval will lead to better quality of life. [...]we strongly believe that the phrase progression-free survival is associated with misunderstanding among patients, which ultimately affects risk–benefit trade-offs. Because the endpoint includes death as a disease-progression event, the term might be technically correct; however, its application has moved far beyond its original role as a tool in early-phase clinical trials, and the phrase is now widely used in the approval of new therapeutics for clinical practice.

Cancer research currently is heavily skewed toward high-income countries (HICs), with little research conducted in, and relevant to, the problems of low- and middle-income countries (LMICs). This regional discordance in cancer knowledge generation and application needs to be rebalanced. Several gaps in the research enterprise of LMICs need to be addressed to promote regionally relevant research, and radical rethinking is needed to address the burning issues in cancer care in these regions. We identified five top priorities in cancer research in LMICs based on current and projected needs: reducing the burden of patients with advanced disease; improving access and affordability, and outcomes of cancer treatment; value-based care and health economics; quality improvement and implementation research; and leveraging technology to improve cancer control. LMICs have an excellent opportunity to address important questions in cancer research that could impact cancer control globally. Success will require collaboration and commitment from governments, policy makers, funding agencies, health care organizations and leaders, researchers and the public. Radical rethinking is needed to address the burning issues in cancer care in low- and middle-income countries. In this Perspective, the authors outline the main challenges and top priorities for cancer research now and into the future.

The combination of a direct electron-detection camera that can count individual electrons and an algorithm for correcting for beam-induced motion in cryo-EM will facilitate determination of three-dimensional structures of smaller, lower-symmetry macromolecular complexes to higher resolution than previously possible. In recent work with large high-symmetry viruses, single-particle electron cryomicroscopy (cryo-EM) has achieved the determination of near-atomic-resolution structures by allowing direct fitting of atomic models into experimental density maps. However, achieving this goal with smaller particles of lower symmetry remains challenging. Using a newly developed single electron–counting detector, we confirmed that electron beam–induced motion substantially degrades resolution, and we showed that the combination of rapid readout and nearly noiseless electron counting allow image blurring to be corrected to subpixel accuracy, restoring intrinsic image information to high resolution (Thon rings visible to ∼3 Å). Using this approach, we determined a 3.3-Å-resolution structure of an ∼700-kDa protein with D7 symmetry, the Thermoplasma acidophilum 20S proteasome, showing clear side-chain density. Our method greatly enhances image quality and data acquisition efficiency—key bottlenecks in applying near-atomic-resolution cryo-EM to a broad range of protein samples.