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BackgroundTo determine the efficacy and toxicity of nivolumab monotherapy in treatment-naïve patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy.MethodsEligible patients with treatment-naïve nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies.Results35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary—1/19 (5%); chromophobe—1/6 (17%); and unclassified—3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of >3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death.ConclusionsNivolumab monotherapy has limited activity in treatment-naïve nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity.Trial registration numberNCT03117309.

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.

A coherent reading of any art work, whatever the medium, requires some detailed awareness of the grid of conventions upon which, and against which, the individual work operates. It is only in exceptional moments of cultural history that these conventions are explicitly codified, as in French neoclassicism or in Arabic and Hebrew poetry of the Andalusian Golden Age, but an elaborate set of tacit agreements between artist and audience about the ordering of the art work is at all times the enabling context in which the complex communication of art occurs. Through our awareness of convention we can recognize significant or simply pleasing patterns of repetition, symmetry, contrast; we can discriminate between the verisimilar and the fabulous, pick up directional clues in a narrative work, see what is innovative and what is deliberately traditional at each nexus of the artistic creation. One of the chief difficulties we encounter as modem readers in

Are the kinds of attention we bring to bear on literature, the skills we use to read it, different from those we exercise in reading other sorts of texts? A generation ago, most critical circles in Europe and America would have answered the question unhesitatingly with a fervent yes. Behind that affirmation stood a long tradition of ideas about literature as a unique repository of values and a uniquely rich vehicle of expression that went back at least to the early nineteenth century or, perhaps further still, to Renaissance apologies for literature like Sir Philip Sidney's Defense of Poetry. Over the past two decades, however, all such "privileging" of literature over other kinds of discourse has come to seem radically suspect. We read literature, the new critics have argued on various grounds, with the same set of complex skills we use to read newspapers, legal rulings, menus, advertisements, sex manuals; and it is only cultural prejudice or ideological conviction that allows us to claim a special truth for literature. For the moment, I would like to concentrate on the issue of how literature is read, leaving the question of truth for separate consideration. It is obvious that there are usually strong continuities between the ways we read literary texts and the ways we read other kinds of texts. If this were not so, we would all need elaborate specialized training, like taking courses in Sanskrit or calculus, in order to make sense of the simplest story or poem. In fact, this sort of sharp split between literary and ordinary language does occasionally occur in the evolution of literary history. Thus, the poetry of medieval Spain in both Ara

The difference of literature character and the connection with reality style allusion structure perspective multiple readings and the bog of indeterminacy. (Part contents)

Perhaps the greatest peculiarity of biblical poetry among the literatures of the ancient Mediterranean world is its seeming avoidance of narrative. The Hebrew writers used verse for celebratory song, dirge, oracle, oratory, prophecy, reflective and didactic argument, liturgy, and often as a heightening or summarizing inset in the prose narratives - but only marginally and minimally to tell a tale. This absence of narrative is all the more striking against the background of the surrounding and antecedent literatures of the ancient Near East that have been uncovered by archeological research. To cite the most apposite example, the literature of the city of Ugarit, on the Mediterranean coast of present-day Syria, written around 1300 B.C.E. in a language closely cognate to biblical Hebrew and according to the same general conventions of poetic parallelism, includes long verse narratives that have recognizably epic features: In an interplay of narration and dialogue, the formal burden of the poetry is the telling of a traditional tale; and the narrative tempo is leisurely enough to allow for detailed descriptions of feasts, hand-to-hand combat, even to some degree of the physical appearance of the actors, human and (for the most part) divine. There is nothing like this in the Hebrew Bible, and supposedly "epic" elements like the historical psalms (Ps. 78, 105, 106) are actually exceptions that confirm the rule, for they turn out to be versified summaries or catechistic rehearsals of Israelite history, with no narrative realization of the events invoked, their intelligibility dependent on the audience's detailed knowledge of the events. And even the rare biblical poems that have explicit narrative segments, like the Song of the Reed Sea and the Song of Deborah, are not, strictly speaking, narrative poems, because they lack the defining feature of independent narrative - exposition - and instead respond to an event or set of events presumably already known to

A Tale of Two Cities has probably given serious critics of Dickens more trouble than any other of his novels. Written at the height of Dickens' artistic maturity, it seems almost willfully to turn away from the very modes of imagination that had made him great and to stress some of the facile formulas that had merely made him popular. From the first, admirers of Dickens have sensed this book to be an uncharacteristic expression of his genius, while Dickens' detractors have seized upon it as a transparent revelation of his general weakness as a novelist. The novel offers good evidence for both views, though the former seems to me on the whole the more cogent of the two. On the one hand, it is clear that Dickens was attempting something new, as he himself confesses in his letters, in treating this whole historical subject. The fact, on the other hand, that the general strategy of this novel differs from that of his other fiction has the effect of leaving certain regrettable conventional elements nakedly exposed which, in the more typical novels, are submerged in the great swirl of brilliant fantastication that can only be called Dickensian. In Little Dorrit, Bleak House, Great Expectations, Our Mutual Friend, the teeming life of Dickensian invention tends to draw our attention away from the imaginative thinness of the heroes and heroines, the contrived coincidences, the strained notes of melodrama, the moments of dewy-eyed, lipserving religiosity, while the more intently dramatic presentation of character and event in A Tale of Two Cities frequently stresses just these qualities. The Tale, then, is conspicuously the uneven work of a writer who, in his greatest novels as well, persists in a kind of splendid, self-transcending unevenness. It is essential, however, to try to see just what he was aiming at in this uncharacteristic book, for his peculiar method of historical fiction here does enable him to make palpable to the imagination a realm of experience that is generally beyond the scope of his other novels. If Dickens' Two Cities in the age of revolution lack the vivid humor and warmth, the intimate feel of bizarre yet familiar British experience, associated with the contemporary England of his other novels, we should not dismiss the Tale for failing to be another Pickwick but should rather seek to understand why Dickens chose to restrict the role in it of just such appealing characteristics. The term Dickens stresses in his correspondence to distinguish the technique of the Tale from that of his previous novels is "picturesque," and that will do nicely for the book if we extend its meaning beyond the limited sense of "dramatic immediacy" which Dickens seems to have had in mind. Most of Dickens' fiction is boldly visual, but the visualization typically concentrates on fascinating