Atezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial.

Stereotactic ablative radiotherapy (SABR) is a standard-of-care for medically-inoperable-early-stage non-small cell lung cancer (NSCLC). One third of patients progress and chemotherapy is rarely used in this population. We questioned if addition of the immune-checkpoint-inhibitor (ICI) atezolizumab to standard-of-care SABR can improve outcomes. We initiated a multi-institutional single-arm phase I study (NCT02599454) enrolling twenty patients with the primary endpoint of maximum tolerated dose (MTD); secondary endpoints of safety and efficacy; and exploratory mechanistic correlatives. Treatment is well tolerated and full dose atezolizumab (1200 mg) is the MTD. Efficacy signals include early responses (after 2 cycles of ICI, before initiation of SABR) in 17% of patients. Biomarkers of functional adaptive immunity, including T cell activation in the tumor and response to ex-vivo stimulation by circulating T cells, are highly predictive of benefit. These results require validation and are being tested in a phase III randomized trial.

Increases in Serial Pretreatment 18F-FDG PET-CT Metrics Predict Survival in Early Stage Non-Small Cell Lung Cancer Treated With Stereotactic Ablative Radiation Therapy.

PURPOSE: Quantitative changes in positron emission tomography with computed tomography imaging metrics over serial scans may be predictive biomarkers. We evaluated the relationship of pretreatment metabolic tumor growth rate (MTGR) and standardized uptake value velocity (SUVV) with disease recurrence or death in patients with early-stage non-small cell lung cancer treated with stereotactic ablative radiation therapy (SABR). METHODS AND MATERIALS: Under institutional review board approval, we retrospectively identified patients who underwent positron emission tomography with computed tomography at diagnosis and staging and simulation for SABR. Two cohorts underwent SABR between November 2005 to October 2012 (discovery) and January 2012 to April 2016 (validation). MTGR and SUVV were calculated as the daily change in metabolic tumor volume and maximum standardized uptake value, respectively. Cox proportional hazard models identified predictors of local, regional, and distant recurrence and death for the combined cohort. MTGR and SUVV thresholds dichotomizing risk of death in the discovery cohort were applied to the validation cohort. RESULTS: A total of 152 lesions were identified in 143 patients (92 lesions in 83 discovery cohort patients). In multivariable models, increasing MTGR trended toward increased hazard of distant recurrence (hazard ratio, 6.98; 95% confidence interval, 0.67-72.61; P = .10). In univariable models, SUVV trended toward risk of death (hazard ratio, 11.8, 95% confidence interval, 0.85-165.1, P = .07). MTGR greater than 0.04 mL/d was prognostic of decreased survival in discovery (P = .048) and validation cohorts (P < .01). CONCLUSIONS: MTGR greater than 0.04 mL/d is prognostic of death in patients with non-small cell lung cancer treated with SABR. Increasing SUVV trends, nonsignificantly, toward increased risk of recurrence and death. MTGR and SUVV may be candidate imaging biomarkers to study in trials evaluating systemic therapy with SABR for patients at high risk of out-of-field recurrence.

Radiation induced lichen planus - an uncommon side effect.

Cutaneous lichen planus is classically characterized by violaceous, pruritic, planar papules and plaques, most commonly affecting the extremities. Lichen planus following radiation therapy is extremely rare and lichen planus following radiation therapy for prostate carcinoma has not been previously reported in the literature. We report a 66-year-old man who presented to the dermatology clinic with a symmetric pruritic eruption affecting the pelvic and gluteal region within two months of radiation therapy targeting the prostate and pelvic lymph nodes for prostate adenocarcinoma. The patient did not have a prior history of lichen planus. Physical examination demonstrated well demarcated, violaceous papules and plaques in a circumferential band-like distribution on the bilateral gluteal, lumbosacral, and pelvic region. In addition, he had a few discrete lesions on the calves and dorsal feet. Punch biopsy revealed an acanthotic epidermis with "saw-tooth" rete ridges and a lichenoid inflammatory infiltrate. A diagnosis of hypertrophic lichen planus was made, reinforcing the importance for clinicians to recognize radiation therapy as a risk factor for developing lichen planus despite no prior history of lichen planus.

Detailed prospective peer review in a community radiation oncology clinic.

PURPOSE: In 2012, we instituted detailed prospective peer review of new cases. We present the outcomes of peer review on patient management and time required for peer review. METHODS AND MATERIALS: Peer review rounds were held 3 to 4 days weekly and required 2 physicians to review pertinent information from the electronic medical record and treatment planning system. Eight aspects were reviewed for each case: 1) workup and staging; 2) treatment intent and prescription; 3) position, immobilization, and simulation; 4) motion assessment and management; 5) target contours; 6) normal tissue contours; 7) target dosimetry; and 8) normal tissue dosimetry. Cases were marked as, "Meets standard of care," "Variation," or "Major deviation." Changes in treatment plan were noted. As our process evolved, we recorded the time spent reviewing each case. RESULTS: From 2012 to 2014, we collected peer review data on 442 of 465 (95%) radiation therapy patients treated in our hospital-based clinic. Overall, 91 (20.6%) of the cases were marked as having a variation, and 3 (0.7%) as major deviation. Forty-two (9.5%) of the cases were altered after peer review. An overall peer review score of "Variation" or "Major deviation" was highly associated with a change in treatment plan (P < .01). Changes in target contours were recommended in 10% of cases. Gastrointestinal cases were significantly associated with a change in treatment plan after peer review. Indicators on position, immobilization, simulation, target contours, target dosimetry, motion management, normal tissue contours, and normal tissue dosimetry were significantly associated with a change in treatment plan. The mean time spent on each case was 7 minutes. CONCLUSIONS: Prospective peer review is feasible in a community radiation oncology practice. Our process led to changes in 9.5% of cases. Peer review should focus on technical factors such as target contours and dosimetry. Peer review required 7 minutes per case.

Story comprehension and the impact of studying on recall in children with attention deficit hyperactivity disorder.

This study examined the impact of studying on story comprehension and recall among children with attention deficit hyperactivity disorder (ADHD). Participants in the study were 36 children with ADHD and 43 nonreferred comparison children ages 7 to 11. The participants listened to 1 of 2 folktales and recalled the story both before and after studying a written version of the story for up to 10 min. The stories had been divided into individual events, and each event was coded for the number of causal connections it had to other story events. Each event was presented on a separate page of the study booklet so that time spent on each event could be recorded. All of the transcribed recalls were coded for which story events the participant correctly recalled. For both groups, recall increased as the number of causal connections increased, but the effect of the number of causal connections on recall was stronger for comparison children than for children with ADHD. The results revealed no group differences in studying behavior. However, when recall before studying was included as a predictor of recall after studying, studying was found to be more effective for higher IQ comparison children than for higher IQ children with ADHD, especially at the highest levels of causal connections. The results offer important leads for the development of academic interventions that are specific to the story-comprehension deficits of children with ADHD.

The effect of anticoagulation with subcutaneously delivered polyethylene glycol conjugated hirudin and recombinant tissue plasminogen activator on recurrent stenosis in the rabbit double-balloon injury model.

Myointimal hyperplasia is the condition usually responsible for recurrent stenosis (restenosis) after endarterectomy, bypass grafting and angioplasty. Its cause is still not known. The present study examined whether inhibition of thrombin by tissue plasminogen activator (r-TPA) or polyethylene glycol recombinant hirudin (PEG-hirudin) could reduce restenosis in an animal model. Restenosis was induced in 20 cholesterol-fed rabbits. The right carotid artery underwent a double-balloon injury while left carotid artery acted as a control. Recombinant tissue plasminogen activator (1 mg kg(-1) s.c.) and PEG-hirudin (0.7 mg kg(-1) s.c.) were given subcutaneously with normal saline acting as a control. Blood levels of PEG-hirudin were measured by both ELISA and an Ecarin (activity) assay. Vessel dimensions were measured in histological sections, obtained from perfusion-fixed tissue, using computerised planimetry. The model reproduced many of the histological changes found in human restenosis, such as intramural thrombus, rupture of the elastic lamina, macrophage infiltration and smooth muscle migration. Reinjury caused an almost three-fold reduction in the area of the lumen (median 0.25 mm(2)) compared with uninjured vessels (median 0.72 mm(2)). The mean plasma levels of PEG-hirudin and r-tPA achieved were 291 ng/ml (S.E.M. 28 ng/ml) and 34 IU/ml (S.E.M. 12 IU/ml), respectively. PEG-hirudin significantly inhibited the effect of balloon injury on luminal area compared with saline-treated controls (0.21 versus 0.44 mm(2), respectively, P<0.05). Recombinant tPA also had a similar inhibitory affect, but this did not reach statistical significance (0.16 versus 0.44 mm(2), respectively, P>0.05). The magnitude of luminal narrowing was significantly reduced by subcutaneous injection of PEG-hirudin. Further studies are required to determine whether this effect can be enhanced by other antithrombins or improved methods of delivery.

Difficulties in comprehending causal relations among children with ADHD: the role of cognitive engagement.

The present study examined whether time spent in long looks (i.e., >or=15 s), an index of cognitive engagement, would account for differences between children with attention deficit hyperactivity disorder (ADHD) and comparison children in understanding causal relations. Children viewed two televised stories, once in the presence of toys and once in their absence. Dependent variables were visual attention and questions tapping factual information and causal relations. Comparison children answered significantly more causal relations questions than did the children with ADHD, but only in the toys-present condition. Four lines of evidence revealed that the difficulties children with ADHD had in answering causal relations questions in the toys-present condition could be linked specifically to this group's decreased time spent in long looks.