Addition of Metastasis-Directed Therapy to Systemic Therapy for Oligometastatic Pancreatic Ductal Adenocarcinoma (EXTEND): A Multicenter, Randomized Phase II Trial.

PURPOSE: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC). METHODS: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response measures. RESULTS: Between March 19, 2019, and February 13, 2023, 41 patients were randomly assigned and 40 were eligible for the primary analysis of PFS (19 patients in the MDT arm; 21 patients in the control arm). At a median follow-up time of 17 months, the median PFS time was 10.3 months (95% CI, 4.6 to 14.0) in the MDT arm versus 2.5 months (95% CI, 1.7 to 5.1) in the control arm. PFS was significantly improved by the addition of MDT to systemic therapy (P = .030 for stratified log-rank test) with a hazard ratio of 0.43 (95% CI, 0.20 to 0.94). No grade ≥3 or greater adverse events related to MDT were observed. Systemic immune activation events were associated with MDT and correlated with improved PFS. CONCLUSION: This study supports the addition of MDT to systemic therapy for patients with oligometastatic PDAC. Induction of systemic immunity is a possible mechanism of benefit. These results warrant confirmatory trials to refine treatment strategy and provide external validation.

Evaluation of response after stereotactic body radiotherapy for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is increasing in incidence due to hepatitis C. Stereotactic body radiotherapy (SBRT) is a noninvasive, effective therapy in the management of liver malignancies. The authors evaluated radiological response in 26 patients with HCC treated with SBRT at Indiana University. METHODS: Between March 2005 and June 2008, 26 patients with HCC who were not surgical candidates were enrolled in a phase 1 to 2 trial. Eligibility criteria included solitary tumors ≤ 6 cm or up to 3 lesions with sum diameters ≤ 6 cm, and well-compensated cirrhosis. All patients had imaging before, at 1 to 3 months, and every 3 to 6 months after SBRT. RESULTS: Patients received 3 to 5 fractions of SBRT. Median SBRT dose was 42 Gray (Gy) (range: 24-48 Gy). Median follow-up was 13 months. Per Response Evaluation Criteria in Solid Tumors (RECIST), 4 patients had a complete response (CR), 15 had a partial response (PR), and 7 achieved stable disease (SD) at 12 months. One patient with SD experienced progression marginal to the treated area. The overall best response rate (CR + PR) was 73%. In comparison, by European Association for the Study of the Liver (EASL) criteria, 18 of 26 patients had ≥ 50% nonenhancement at 12 months. Thirteen of 18 demonstrated 100% nonenhancement, being > 50% in 5 patients. Kaplan-Meier 1- and 2-year survival estimates were 77% and 60%, respectively. CONCLUSIONS: SBRT is effective therapy for patients with HCC with an overall best response rate (CR + PR) of 73%. Nonenhancement on imaging, a surrogate for ablation, may be a more useful indicator than size reduction in evaluating HCC response to SBRT in the first 6 to 12 months, supporting EASL criteria.

Development of object concepts in macaque monkeys.

One of the most interesting questions in cognitive development is how we acquire and mentally represent knowledge about objects. We investigated the development of object concepts in macaque monkeys. Monkeys viewed trajectory occlusion movies in which a ball followed a linear path that was occluded for some portion of the display while their point of gaze was recorded with a corneal-reflection eye tracker. We analyzed the pattern of eye movements as an indicator of object representation. A majority of eye movements of adult monkeys were anticipatory, implying a functional internal object representation that guided oculomotor behavior. The youngest monkeys lacked this strong internal representation of objects. Longitudinal testing showed that this ability develops over time providing compelling evidence that object concepts develop similarly in monkeys and humans. Therefore, the macaque monkey provides an animal model with which to examine neural mechanisms underlying the development of object representations.

The use of restraint and seclusion in different racial groups in an inpatient forensic setting.

The purpose of this study was to determine if physical restraint and/or seclusion had been used with different frequencies in patients of different racial groups in an inpatient forensic psychiatry facility. The method used was a retrospective correlational study of all inpatients (n = 806) treated from January 1993 through August 2000 at Kirby Forensic Psychiatric Center, a maximum-security inpatient forensic facility in Ward's Island, NY, near New York City. Episodes of restraint and/or seclusion were measured in each racial group. The number of violent incidents involving patients of each racial group was also measured. Racial groups at Kirby did not differ significantly from each other in number of violent incidents nor in the number of episodes of restraints. However, Asians and blacks as racial groups were more likely to have been secluded than were other racial groups. This difference did not persist when the number of incidents of seclusion was considered individually rather than for entire racial groups.

Development of sensitivity to global form and motion in macaque monkeys (Macaca nemestrina).

To explore the relative development of the dorsal and ventral extrastriate processing streams, we studied the development of sensitivity to form and motion in macaque monkeys (Macaca nemestrina). We used Glass patterns and random dot kinematograms (RDK) to assay ventral and dorsal stream function, respectively. We tested 24 animals, longitudinally or cross-sectionally, between the ages of 5 weeks and 3 years. Each animal was tested with Glass patterns and RDK stimuli with each of two pattern types--circular and linear--at each age using a two alternative forced-choice task. We measured coherence threshold for discrimination of the global form or motion pattern from an incoherent control stimulus. Sensitivity to global motion appeared earlier than to global form and was higher at all ages, but performance approached adult levels at similar ages. Infants were most sensitive to large spatial scale (Δx) and fast speeds; sensitivity to fine scale and slow speeds developed more slowly independently of pattern type. Within the motion domain, pattern type had little effect on overall performance. However, within the form domain, sensitivity for linear Glass patterns was substantially poorer than that for concentric patterns. Our data show comparatively early onset for global motion integration ability, perhaps reflecting early development of the dorsal stream. However, both pathways mature over long time courses reaching adult levels between 2 and 3 years after birth.

Imaging changes after stereotactic body radiation therapy for lung and liver tumors.

Stereotactic body radiation therapy (SBRT) is gaining wide acceptance as a treatment modality for lung and liver tumors, and it is crucial to make an accurate evaluation of the local effects of ablative doses of radiation in terms of local tumor control and normal tissue reaction or damage. The very complex radiation dose distribution of SBRT, the use of a large number of non-opposing and noncoplanar beams, and the delivery of individual ablative doses of radiation may cause substantially different radiographic appearance on diagnostic imaging compared with conventional radiation therapy. Different patterns of radiographic changes have been observed in the lung and liver after SBRT. This article reviews the post-SBRT imaging changes in the lung and liver. Since computed tomography and PET are the most commonly used diagnostic imaging tools for monitoring lung tumor and computed tomography for liver tumors, this article will focus on the changes observed on those imaging modalities.

Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is increasing in incidence and the majority of patients are not candidates for radical therapies. Therefore, interest in minimally invasive therapies in growing. METHODS: A Phase I dose escalation trial was conducted at Indiana University to determine the feasibility and toxicity of stereotactic body radiation therapy (SBRT) for primary HCC. Eligible patients had Child-Turcotte-Pugh's Class (CTP) A or B, were not candidates for resection, had 1-3 lesions and cumulative tumour diameter less than or equal to 6 cm. Dose escalation started at 36 Gy in 3 fractions (12 Gy/fraction) with a subsequent planned escalation of 2 Gy/ fraction/level. Dose-limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events v3.0 grade 3 or greater toxicity. RESULTS: Seventeen patients with 25 lesions were enrolled. Dose was escalated to 48 Gy (16 Gy/fraction) in CTP-A patients without DLT. Two patients with CPC-B disease developed grade 3 hepatic toxicity at the 42-Gy (14 Gy/fraction) level. The protocol was amended for subsequent CTP-B patients to receive a regimen of 5 fractions starting at 40 Gy (8 Gy/fraction) with one patient experiencing progressive liver failure. Four additional patients were enrolled (one died of unrelated causes after an incomplete SBRT course) without DLT. The only factor related to more than one grade 3 or greater liver toxicity or death within 6 months was the CTP score (p=0.03). Six patients underwent a liver transplant. Ten patients are alive without progression with a median FU of 24 months (10-42 months), with local control/stabilisation of the disease of 100%. One and two-year Kaplan-Meier estimates for overall survival are 75% and 60%, respectively. CONCLUSIONS: SBRT is a non-invasive feasible and well tolerated therapy in adequately selected patients with HCC. The preliminary local control and survival are encouraging. A confirmatory Phase II trial is currently open to accrual.

A neurochemical signature of visual recovery after extrastriate cortical damage in the adult cat.

In adult cats, damage to the extrastriate visual cortex on the banks of the lateral suprasylvian (LS) sulcus causes severe deficits in motion perception that can recover as a result of intensive direction discrimination training. The fact that recovery is restricted to trained visual field locations suggests that the neural circuitry of early visual cortical areas, with their tighter retinotopy, may play an important role in attaining perceptual improvements after damage to higher level visual cortex. The present study tests this hypothesis by comparing the manner in which excitatory and inhibitory components of the supragranular circuitry in an early visual cortical area (area 18) are affected by LS lesions and postlesion training. First, the proportion of LS-projecting pyramidal cells as well as calbindin- and parvalbumin-positive interneurons expressing each of the four AMPA receptor subunits was estimated in layers II and III of area 18 in intact animals. The degree to which LS lesions and visual retraining altered these expression patterns was then assessed. Both LS-projecting pyramidal cells and inhibitory interneurons exhibited long-term, differential reductions in the expression of glutamate receptor (GluR)1, -2, -2/3, and -4 following LS lesions. Intensive visual training post lesion restored normal AMPAR subunit expression in all three cell-types examined. Furthermore, for LS-projecting and calbindin-positive neurons, this restoration occurred only in portions of the ipsi-lesional area 18 representing trained visual field locations. This supports our hypothesis that stimulation of early visual cortical areas-in this case, area 18-by training is an important factor in restoring visual perception after permanent damage to LS cortex.