Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.

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Given the joint occurrence of positive attitudinal and learning effects that typically result from repeated stimulus exposure, most researchers have concluded that what an individual knows and what he or she feels about the familiar stimulus are not independent. In fact, it is generally assumed that some form of learning, such as recognition, both precedes and mediates the affective response. This study questioned that assumption by seeking to obtain positive exposure effects in the absence of stimulus recognition. In order to unconfound affect and learning effects, two experiments with female subjects employed a dichotic-listening procedure for stimulus exposure, in which the critical stimuli were exposed on the unattended channel. Reliable attitudinal enhancement toward objectively familiar stimuli was obtained in both experiments, even though recognition levels were low (Experiment 1) or at chance levels (Experiment 2). Subjective stimulus familiarity was not found to be a significant predictor of affect in either experiment. Positive feelings toward a previously encountered object are not dependent on consciously knowing or perceiving that the object is familiar. Implications for the role of awareness in processes of attitude formation under conditions of mere exposure are discussed.Research on the cognitive and affective changes that an individual experiences as a function of repeated stimulus exposure has consistently obtained two results. At a cogni-

Discrimination between individual strangers and companions was examined in day-old domestic chicks. In one experiment, pecking rates at companions and strangers were observed in pairwise bouts after 16 hr of cohabitation. The discriminability of strangers and companions was varied by means of pre-hatch colouring. Reliable discriminations between individual strangers and companions emerged as early as the first minute of the encounter. Discriminative cues provided by artificial colouring were found not to be necessary in establishing social discrimination. In a second experiment, undyed chicks were housed in pairs for 1, 4 or 16 hr. Half of the pairs lived in cages that separated companions by a wire screen, and half were housed in undivided cages. Observations of pecking in four-way bouts confirmed previous findings and demonstrated that the opportunity to peck during exposure may be a necessary condition in producing social discrimination. Antecedent conditions that lead to the development of affiliative bonds simultaneously appear to establish social discrimination.

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