Moving the Needle Forward in Genomically-Guided Precision Radiation Treatment.

Radiation treatment (RT) is a mainstay treatment for many types of cancer. Recommendations for RT and the radiation plan are individualized to each patient, taking into consideration the patient's tumor pathology, staging, anatomy, and other clinical characteristics. Information on germline mutations and somatic tumor mutations is at present rarely used to guide specific clinical decisions in RT. Many genes, such as ATM, and BRCA1/2, have been identified in the laboratory to confer radiation sensitivity. However, our understanding of the clinical significance of mutations in these genes remains limited and, as individual mutations in such genes can be rare, their impact on tumor response and toxicity remains unclear. Current guidelines, including those from the National Comprehensive Cancer Network (NCCN), provide limited guidance on how genetic results should be integrated into RT recommendations. With an increasing understanding of the molecular underpinning of radiation response, genomically-guided RT can inform decisions surrounding RT dose, volume, concurrent therapies, and even omission to further improve oncologic outcomes and reduce risks of toxicities. Here, we review existing evidence from laboratory, pre-clinical, and clinical studies with regard to how genetic alterations may affect radiosensitivity. We also summarize recent data from clinical trials and explore potential future directions to utilize genetic data to support clinical decision-making in developing a pathway toward personalized RT.

Tumors of the brachial plexus region: A 15-year experience with emphasis on motor and pain outcomes and literature review.

Background: Brachial plexus region tumors are rare. In this study, we reviewed our experience with resection of tumors involving or adjacent to the brachial plexus to identify patterns in presentation and outcome. Methods: We report a retrospective case series of brachial plexus tumors operated on by a single surgeon at a single institution over 15 years. Outcome data were recorded from the most recent follow-up office visit. Findings were compared to a prior internal series and comparable series in the literature. Results: From 2001 to 2016, 103 consecutive brachial plexus tumors in 98 patients met inclusion criteria. Ninety percent of patients presented with a palpable mass, and 81% had deficits in sensation, motor function, or both. Mean follow-up time was 10 months. Serious complications were infrequent. For patients with a preoperative motor deficit, the rate of postoperative motor decline was 10%. For patients without a preoperative motor deficit, the rate of postoperative motor decline was 35%, which decreased to 27% at 6 months. There were no differences in motor outcome based on extent of resection, tumor pathology, or age. Conclusion: We present one of the largest recent series of tumors of the brachial plexus region. Although the rate of worsened postoperative motor function was higher in those without preoperative weakness, the motor deficit improves over time and is no worse than antigravity strength in the majority of cases. Our findings help guide patient counseling in regard to postoperative motor function.

The phase of plasticity-induced neurochemical changes of high-frequency repetitive transcranial magnetic stimulation are different from visual perceptual learning.

Numerous studies have found that repetitive transcranial magnetic stimulation (rTMS) modulates plasticity. rTMS has often been used to change neural networks underlying learning, often under the assumption that the mechanism of rTMS-induced plasticity should be highly similar to that associated with learning. The presence of visual perceptual learning (VPL) reveals the plasticity of early visual systems, which is formed through multiple phases. Hence, we tested how high-frequency (HF) rTMS and VPL modulate the effect of visual plasticity by investigating neurometabolic changes in early visual areas. We employed an excitatory-to-inhibitory (E/I) ratio, which refers to glutamate concentration divided by GABA+ concentration, as an index of the degree of plasticity. We compared neurotransmitter concentration changes after applying HF rTMS to the visual cortex with those after training in a visual task, in otherwise identical procedures. Both the time courses of the E/I ratios and neurotransmitter contributions to the E/I ratio significantly differed between HF rTMS and training conditions. The peak E/I ratio occurred 3.5 h after HF rTMS with decreased GABA+, whereas the peak E/I ratio occurred 0.5 h after visual training with increased glutamate. Furthermore, HF rTMS temporally decreased the thresholds for detecting phosphene and perceiving low-contrast stimuli, indicating increased visual plasticity. These results suggest that plasticity in early visual areas induced by HF rTMS is not as involved in the early phase of development of VPL that occurs during and immediately after training.

Dietary Interventions in Cancer Treatment and Response: A Comprehensive Review.

Chemotherapy and radiotherapy are first-line treatments in the management of advanced solid tumors. Whereas these treatments are directed at eliminating cancer cells, they cause significant adverse effects that can be detrimental to a patient's quality of life and even life-threatening. Diet is a modifiable risk factor that has been shown to affect cancer risk, recurrence, and treatment toxicity, but little information is known how diet interacts with cancer treatment modalities. Although dietary interventions, such as intermittent fasting and ketogenic diets, have shown promise in pre-clinical studies by reducing the toxicity and increasing the efficacy of chemotherapeutics, there remains a limited number of clinical studies in this space. This review surveys the impact of dietary interventions (caloric restriction, intermittent and short-term fasting, and ketogenic diet) on cancer treatment outcomes in both pre-clinical and clinical studies. Early studies support a complementary role for these dietary interventions in improving patient quality of life across multiple cancer types by reducing toxicity and perhaps a benefit in treatment efficacy. Larger, phase III, randomized clinical trials are ultimately necessary to evaluate the efficacy of these dietary interventions in improving oncologic or quality of life outcomes for patients that are undergoing chemotherapy or radiotherapy.

A novel kinase subverts aluminium resistance by boosting ornithine decarboxylase-dependent putrescine biosynthesis.

Rice, as one of the most aluminium (Al)-resistant cereal crops, has developed more complicated Al resistance mechanisms than others. By using forward genetic screening from a rice ethyl methanesulfonate mutant library, we obtained a mutant showing specifically high sensitivity to Al. Through MutMap analysis followed by a complementation test, we identified the causal gene, Al-related Protein Kinase (ArPK) for Al-sensitivity. ArPK expression was induced by a relatively longer exposure to high Al concentration in the roots. The result of RNA-sequencing indicated the functional disorder in arginine metabolism pathway with downregulation of N-acetylornithine deacetylase (NAOD) expression and upregulation of Ornithine decarboxylase1 (ODC1) expression in arpk mutant. Al specifically and rapidly upregulated ODC1 expression and causes overaccumulation of putrescine (Put), whereas the ODC inhibitor difluoromethylornithine reverted Al-sensitive phenotype of arpk, suggesting that overaccumulation of endogenous Put might be harmful for root growth, and that ArPK seems to act as an endogenous inhibitor of ODC1 action to maintain suitable endogenous Put level under Al treatment. Overall, we identified ArPK and its putative repressive role in controlling a novel ODC-dependent Put biosynthesis pathway specifically affecting rice Al resistance, thus enriching the fundamental understanding of plant Al resistance.

Baseline Cerebro-Cerebellar Functional Connectivity in Afferent and Efferent Pathways Reveal Dissociable Improvements in Visuomotor Learning.

Visuomotor coordination is a complex process involving several brain regions, primarily the cerebellum and motor cortex. Studies have shown inconsistent resting-state functional magnetic resonance imaging (rsfMRI) results in the cerebellar cortex and dentate nucleus of the cerebro-cerebellar connections. Echoing anatomical pathways, these two different cerebellar regions are differentially responsible for afferent and efferent cerebro-cerebellar functional connections. The aim of this study was to measure the baseline resting-state functional connectivity of different cerebellar afferent and efferent pathways and to investigate their relationship to visuomotor learning abilities. We used different cerebellar repetitive transcranial magnetic stimulation (rTMS) frequencies before a pursuit rotor task to influence visuomotor performance. Thirty-eight right-handed participants were included and randomly assigned to three different rTMS frequency groups (1 Hz, 10 Hz and sham) and underwent baseline rsfMRI and pursuit rotor task assessments. We report that greater baseline functional connectivity in the afferent cerebro-cerebellar pathways was associated with greater accuracy improvements. Interestingly, lower baseline functional connectivity in the efferent dentato-thalamo-cortical pathways was associated with greater stability in visuomotor performance, possibly associated with the inhibitory role of the dentate nucleus and caused a reduction in the efferent functional connectivity. The functional dissociation of the cerebellar cortex and dentate nucleus and their connections, suggests that distinct mechanisms in the cerebellum regarding visuomotor learning, which should be investigated in future research.

Frequency-Dependent Effects of Cerebellar Repetitive Transcranial Magnetic Stimulation on Visuomotor Accuracy.

The cerebellum plays a critical role in acquiring visuomotor skills. Visuomotor task mastery requires improving both visuomotor accuracy and stability; however, the cerebellum's contribution to these processes remains unclear. We hypothesized that repetitive transcranial magnetic stimulation (rTMS) of the cerebellum exerts frequency-dependent modulatory effects on both accuracy and stability in subjects performing a visuomotor coordination task (i.e., pursuit rotor task). We recruited 43 healthy volunteers and randomly assigned them to the high-frequency (HF), low-frequency (LF), and sham rTMS groups. We calculated changes in performance of the pursuit rotor task at the highest rotation speed and the minimum distance from target as indices of accuracy. We also calculated the intertrial variability (standard deviations) of time on target and distance from target as indices of stability. Visuomotor accuracy was significantly enhanced in the HF group and disrupted in the LF group compared to the sham group, indicating frequency-dependent effects of rTMS. In contrast, both HF and LF rTMS demonstrated no significant change in visuomotor stability. Surprisingly, our findings demonstrated that the accuracy and stability of visuomotor performance may be differentially influenced by cerebellar rTMS. This suggests that visuomotor accuracy and stability have different underlying neural mechanisms and revealed the possibility of training strategies based on cerebellar neuromodulation.

Identification of Novel Loci Shared by Juvenile Idiopathic Arthritis Subtypes Through Integrative Genetic Analysis.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common chronic immune-mediated joint disease among children and encompasses a heterogeneous group of immune-mediated joint disorders classified into 7 subtypes according to clinical presentation. However, phenotype overlap and biologic evidence suggest a shared mechanistic basis between subtypes. This study was undertaken to systematically investigate shared genetic underpinnings of JIA subtypes. METHODS: We performed a heterogeneity-sensitive genome-wide association study encompassing a total of 1,245 JIA cases (classified into 7 subtypes) and 9,250 controls, followed by fine-mapping of candidate causal variants at each genome-wide significant locus, functional annotation, and pathway and network analysis. We further identified candidate drug targets and drug repurposing opportunities by in silico analyses. RESULTS: In addition to the major histocompatibility complex locus, we identified 15 genome-wide significant loci shared between at least 2 JIA subtypes, including 10 novel loci. Functional annotation indicated that candidate genes at these loci were expressed in diverse immune cell types. CONCLUSION: This study identified novel genetic loci shared by JIA subtypes. Our findings identified candidate mechanisms underlying JIA subtypes and candidate targets with drug repurposing opportunities for JIA treatment.

Pre-operative partial breast irradiation: revolutionizing radiation treatment for women with early stage breast cancer.

Partial breast irradiation (PBI) has been increasingly accepted as a suitable component of breast conservation in the management of patients with early stage breast cancer, however the majority of existing studies have focused on the use of adjuvant or intra-operative techniques. Several early stage studies have more recently shown that PBI can be safely used in the pre-operative setting. Early data show similar local control without evidence of increased toxicity or worsening cosmesis, as compared to postoperative PBI or standard whole breast irradiation. While long term data are still maturing, pre-operative accelerated PBI (PAPBI) offers a number of possible clinical advantages including reducing the treatment field and increasing the number of patients eligible for PBI, identifying biomarkers of response to radiation, and improving the rates of breast conservation and treatment compliance. This review discusses key concepts and controversies surrounding PBI as it has increasingly been adopted in the US, Canada, and Europe, and introduces the concepts and early studies of PAPBI. In addition, we summarize ongoing clinical trials investigating PAPBI, review clinical benefits and challenges associated with PAPBI versus postoperative PBI, and discuss ongoing limitations as well as next generation technologies important to the implementation of PAPBI in the management of patients with early-stage localized breast cancer.

Pan-Cancer Survival Classification With Clinicopathological and Targeted Gene Expression Features.

Prognostication for patients with cancer is important for clinical planning and management, but remains challenging given the large number of factors that can influence outcomes. As such, there is a need to identify features that can robustly predict patient outcomes. We evaluated 8608 patient tumor samples across 16 cancer types from The Cancer Genome Atlas and generated distinct survival classifiers for each using clinical and histopathological data accessible to standard oncology workflows. For cancers that had poor model performance, we deployed a random-forest-embedded sequential forward selection approach that began with an initial subset of the 15 most predictive clinicopathological features before sequentially appending the next most informative gene as an additional feature. With classifiers derived from clinical and histopathological features alone, we observed cancer-type-dependent model performance and an area under the receiver operating curve (AUROC) range of 0.65 to 0.91 across all 16 cancer types for 1- and 3-year survival prediction, with some classifiers consistently outperforming those for others. As such, for cancers that had poor model performance, we posited that the addition of more complex biomolecular features could enhance our ability to prognose patients where clinicopathological features were insufficient. With the inclusion of gene expression data, model performance for 3 select cancers (glioblastoma, stomach/gastric adenocarcinoma, ovarian serous carcinoma) markedly increased from initial AUROC scores of 0.66, 0.69, and 0.67 to 0.76, 0.77, and 0.77, respectively. As a whole, this study provides a thorough examination of the relative contributions of clinical, pathological, and gene expression data in predicting overall survival and reveals cancer types for which clinical features are already strong predictors and those where additional biomolecular information is needed.

Sex-based differences in bacterial meningitis in adults: Epidemiology, clinical features, and therapeutic outcomes.

BACKGROUND: To investigate the sex-based differences in clinical features, causative pathogens, and outcomes of hospital-based culture-proven adult bacterial meningitis. OBJECTIVE: This retrospective study enrolled 621 patients at a tertiary medical center. To compare changes over time, the presentation of disease among the enrolled patients was divided into two equal time periods: the first study period (1986-2002) and the second study period (2003-2019). RESULTS: Of the 621 patients enrolled in this study, 396 were males and 225 were females. The overall case fatality rate was 30.4% with 30.1% and 31.1% in males and females, respectively. Regarding the causative pathogens, there was a rising incidence of coagulase-negative staphylococcal infections and a decreasing incidence of Klebsiella pneumoniae infection in both male and female in the second study period. The prevalence of patients with nosocomial infection in a postneurosurgical state were 41.9% (68/162) in the first study period and 58.1% (94/162) in the second study period in male group, and 34.8% (32/92) in the first study period and 65.2% (60/92) in the second study period in female group, respectively. Significant factors between the sexes difference included age (P = 0.004), traumatic brain injury (P = 0.01), alcoholism (P < 0.001), brain tumor (P < 0.001), systemic lupus erythematosus (SLE) (P = 0.004), presence of diabetic ketoacidosis/hyperglycemic hyperosmolar state (P = 0.033), brain abscess (P = 0.042), and total protein (P = 0.002) and white blood cell count (P = 0.036) of cerebrospinal fluid data. CONCLUSION: Our study revealed an increase in the number of patients with nosocomial infection with a postneurosurgical state in both male and female in the second study period. Males were younger and frequently presented with a history of head trauma and alcoholism with concomitant brain abscesses while females presented with SLE and brain tumor. The therapeutic outcome did not show differences between the sexes.

ANKRD11 variants: KBG syndrome and beyond.

Mutations affecting the transcriptional regulator Ankyrin Repeat Domain 11 (ANKRD11) are mainly associated with the multisystem developmental disorder known as KBG syndrome, but have also been identified in individuals with Cornelia de Lange syndrome (CdLS) and other developmental disorders caused by variants affecting different chromatin regulators. The extensive functional overlap of these proteins results in shared phenotypical features, which complicate the assessment of the clinical diagnosis. Additionally, re-evaluation of individuals at a later age occasionally reveals that the initial phenotype has evolved toward clinical features more reminiscent of a developmental disorder different from the one that was initially diagnosed. For this reason, variants in ANKRD11 can be ascribed to a broader class of disorders that fall within the category of the so-called chromatinopathies. In this work, we report on the clinical characterization of 23 individuals with variants in ANKRD11. The subjects present primarily with developmental delay, intellectual disability and dysmorphic features, and all but two received an initial clinical diagnosis of either KBG syndrome or CdLS. The number and the severity of the clinical signs are overlapping but variable and result in a broad spectrum of phenotypes, which could be partially accounted for by the presence of additional molecular diagnoses and distinct pathogenic mechanisms.

Is there an association between body mass index and 21-gene recurrence score?

PURPOSE: The 21-gene recurrence score (RS) is an established predictor of recurrence for early stage, hormone receptor positive breast cancer. The association between RS and other risk factors such as obesity has not been fully explored. We hypothesized that patients with obesity may present with primary breast cancers with higher recurrence scores. METHODS: We identified 1546 patients who have body mass index (BMI) recorded around the time of RS assay. Obesity was classified as per CDC definitions of overweight (BMI 25-30 kg/m2) and obesity (BMI >30 kg/m2). RS was assessed as a continuous variable and according to pre- and post-TAILORx classifications. Kaplan Meier survival analysis was employed to assess the interaction between RS and BMI on overall survival (OS) and disease-free survival (DFS). RESULTS: In univariate analyses, the median RS in patients with overweight was 15, which was significantly lower than the median RS (16) of patients with normal weight (p = 0.03). The overall recurrence rate of patients with obesity was 4.1%, which was significantly worse than the overall recurrence rate of patients with normal and overweight of 2.6% and 1.5%, respectively (p = 0.05). In multivariate analyses using the inverse probability weighted regression adjustment (IPWRA) method to adjust for imbalances between subgroups, patients with overweight or obesity had significantly lower RS than patients with normal weight, correlating to an average decrease in RS value of 2.37 and 1.71, respectively (both p < 0.01). A similar relationship was seen between BMI categories and RS as a categorical variable stratified according to pre- or post-TAILORx categories. This inverse effect was predominantly seen in post-menopausal patients. Despite the generally lower RS in patients with obesity, a high RS in these patients is associated with diminished DFS (p = 0.04). CONCLUSION: Tumors in post-menopausal women with higher BMI generally have lower RS. DFS is significantly worse in women with obesity whose RS ≥ 30. The reasons for poor outcomes for postmenopausal patients with obesity despite lower presenting RS merits further study.

Genomic risk scores for juvenile idiopathic arthritis and its subtypes.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is an autoimmune disease and a common cause of chronic disability in children. Diagnosis of JIA is based purely on clinical symptoms, which can be variable, leading to diagnosis and treatment delays. Despite JIA having substantial heritability, the construction of genomic risk scores (GRSs) to aid or expedite diagnosis has not been assessed. Here, we generate GRSs for JIA and its subtypes and evaluate their performance. METHODS: We examined three case/control cohorts (UK, US-based and Australia) with genome-wide single nucleotide polymorphism (SNP) genotypes. We trained GRSs for JIA and its subtypes using lasso-penalised linear models in cross-validation on the UK cohort, and externally tested it in the other cohorts. RESULTS: The JIA GRS alone achieved cross-validated area under the receiver operating characteristic curve (AUC)=0.670 in the UK cohort and externally-validated AUCs of 0.657 and 0.671 in the US-based and Australian cohorts, respectively. In logistic regression of case/control status, the corresponding odds ratios (ORs) per standard deviation (SD) of GRS were 1.831 (1.685 to 1.991) and 2.008 (1.731 to 2.345), and were unattenuated by adjustment for sex or the top 10 genetic principal components. Extending our analysis to JIA subtypes revealed that the enthesitis-related JIA had both the longest time-to-referral and the subtype GRS with the strongest predictive capacity overall across data sets: AUCs 0.82 in UK; 0.84 in Australian; and 0.70 in US-based. The particularly common oligoarthritis JIA also had a GRS that outperformed those for JIA overall, with AUCs of 0.72, 0.74 and 0.77, respectively. CONCLUSIONS: A GRS for JIA has potential to augment clinical JIA diagnosis protocols, prioritising higher-risk individuals for follow-up and treatment. Consistent with JIA heterogeneity, subtype-specific GRSs showed particularly high performance for enthesitis-related and oligoarthritis JIA.

Does Alzheimer's Disease and Related Dementias Modify Delirium Severity and Hospital Outcomes?

OBJECTIVES: We examined the association between delirium severity and outcomes of delirium among persons with and without Alzheimer's disease and related dementias (ADRD). DESIGN: Prospective cohort study. SETTING: Academic tertiary medical center. PARTICIPANTS: A total of 352 medical and surgical patients. MEASUREMENTS: Delirium incidence and severity were rated daily using the Confusion Assessment Method (CAM) and CAM-Severity (CAM-S) score during hospitalization. Severe delirium was defined as a CAM-S Short Form score in the highest tertile (3-7 points out of 7). ADRD status was determined by a clinical consensus process. Clinical outcomes included prolonged length of stay (>6 d), discharge to post-acute nursing facility, any decline in activities of daily living (ADLs) at 1 month from prehospital baseline, ongoing nursing facility stay, and mortality. RESULTS: Patients with ADRD (n = 85 [24%]) had a significantly higher relative risk (RR) for incident delirium (RR = 2.31; 95% confidence interval [CI] = 1.64-3.28) and higher peak CAM-S scores (mean difference = 1.24 points; CI = .83-1.65; P < .001). Among patients with ADRD, severe delirium significantly increased the RR for nursing facility stay (RR = 2.22; CI = 1.05-4.69; P = .04) and increased the RR for mortality (RR = 2.10; CI = .89-4.98; P = .09). Among patients without ADRD, severe delirium was associated with a significantly increased risk for all poor outcomes except mortality including prolonged length of stay in the hospital (RR = 1.47; CI = 1.18-1.82) and discharge to a post-acute nursing facility (RR = 2.17; CI = 1.58-2.98) plus decline in ADLs (RR = 1.30; CI = 1.05-1.60) and nursing facility stay at 1 month (RR = 1.93; CI = 1.31-2.83). CONCLUSION: Severe delirium is associated with increased risk for poor clinical outcomes in patients with and without ADRD. In both groups, severe delirium increased risk of nursing home placement. In patients with ADRD, delirium was more severe and associated with a trend toward increased mortality at 1 month. Although the increased risk remains substantial by RR, the study had limited power to examine the rarer outcome of death. J Am Geriatr Soc 68:1722-1730, 2020.

A Novel Method of Nasojejunal Feeding and Gastric Decompression Using a Double Lumen Silicone Tube for Upper Gastrointestinal Obstruction.

BACKGROUND: Provision of enteral nutrition with jejunal feeding in upper gastrointestinal obstruction is highly recommended. Access to jejunum can be obtained surgically, percutaneously, or endoscopically. Our institution routinely and preferentially utilizes a silicone nasojejunal tube that is inserted past the obstruction endoscopically. We use a custom dual channel tube that allows feeding at the distal tip and another channel 40 cm from the tip that enables decompression proximally. This is a report of our experience with this custom nasojejunal tube. METHODS: This is a prospective observational study of 201 patients who underwent endoscopic nasojejunal wire-guided feeding tube insertions for obstruction of either the esophagus or the stomach including both benign and malignant pathologies between January 2015 to June 2018 in Hospital Sungai Buloh and Hospital Sultanah Aminah, Malaysia. The indications for tube insertion, insertion technique, and tube-related problems were described. RESULTS: The nasojejunal tube was used to establish enteral feeding in patients with obstructing tumors of the distal esophagus in 65 patients (32.3%) and gastric outlet obstruction in 72 patients (35.8%). There were 54 patients (26.9%) who required reinsertion. The most common reason for reinsertion was unintentional dislodgement, where 32 patients (15.9%) followed by tube blockage 20 patients (10.0%). Using our method of advancement under direct vision, we had only 2 cases of malposition due to severely deformed anatomy. We had no incidence of aspiration in this group of patients and overall, the patients tolerated the tube well. CONCLUSIONS: The novel nasojejunal feeding tube with gastric decompression function is a safe and effective method of delivery of enteral nutrition in patients with upper gastrointestinal obstruction. These tubes if inserted properly are well tolerated with almost no risk of malposition and are tolerated well even for prolonged periods of time until definitive surgery could be performed.

A Novel Prospective Study Assessing the Combination of Photodynamic Therapy and Proton Radiation Therapy: Safety and Outcomes When Treating Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma remains difficult to treat, with high failure rates despite optimal therapy. We present a novel prospective trial combining proton therapy (PT) and photodynamic therapy (PDT) and the largest-ever mesothelioma PT experience (n = 10). PDT photosensitizers included porfimer sodium (2 mg·kg-1 ; 24 h drug-light interval) or 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) (4 mg·m-2 ;48 h) with wavelengths of 630 nm to 60J·cm-2 and 665 nm to 15-45J·cm-2 , respectively. With a median age of 69 years, patients were predominantly male (90%) with epithelioid histology (100%) and stage III-IV disease (100%). PT was delivered to a median of 55.0 CGE/1.8-2.0 CGE (range 50-75 CGE) adjuvantly (n = 8) or as salvage therapy (n = 2) following extended pleurectomy/decortication (ePD)/PDT. Two-year local control was 90%, with distant and regional failure rates of 50% and 30%, respectively. All patients received chemotherapy, and four received immunotherapy. Surgical complications included atrial fibrillation (n = 3), pneumonia (n = 2), and deep vein thrombosis (n = 2). Median survival from PT completion was 19.5 months (30.3 months from diagnosis), and 1- and 2-year survival rates were 58% and 29%. No patient experienced CTCAEv4 grade ≥2 acute or late toxicity. Our prolonged survival in very advanced-stage patients compares favorably to survival for PT without PDT and photon therapy with PDT, suggesting possible spatial or systemic cooperativity and immune effect.

The Better Assessment of Illness Study for Delirium Severity: Study Design, Procedures, and Cohort Description.

BACKGROUND/OBJECTIVES: To describe the design, procedures, and cohort for the Better ASsessment of ILlness -(BASIL) study, which is conducted to develop and test new delirium severity measures, compare them with existing measures, and examine related clinical outcomes. METHODS: Prospective cohort study with 1 year follow-up of study participants at a large teaching hospital in Boston, Massachusetts. After brief cognitive testing and the Delirium Symptom Interview, delirium and delirium severity were rated daily in the hospital using the Confusion Assessment Method (CAM) and CAM-Severity score, the Delirium Rating Scale-Revised-98 (DRS-R-98), and the Memorial Delirium Assessment Scale (MDAS). Other key study variables included comorbidity, physical function (basic and instrumental activities of daily living [ADL]), ratings of subjective health and well-being, and clinical outcomes (length of stay, 30 day rehospitalization, nursing home admission, healthcare utilization). Follow-up interviews occurred at 1- and 12-month with patients and families. In 42 patient interviews, inter-rater reliability for key variables was assessed. RESULTS: Of 768 eligible patients approached, 469 were screened and 352 enrolled, yielding an overall study response rate of 67% for potentially eligible participants. The mean participant was 80.3 years old (SD 6.8) and 203 (58%) were female. The majority of patients were medically complex with Charlson Comorbidity Scores ≥2 (192 patients, 55%), and 102 (29%) met criteria for dementia. Inter-rater reliability assessments (n = 42 pairs) were high for overall ratings of presence or absence of delirium by CAM (κ = 1.0), delirium severity by DRS-R-98 and MDAS (weighted kappa, κ = 1.0 for each) and for ADL impairment (κ = 1.0). For eligible participants at each time point, 278 out of 308 (90%) completed the 1-month follow-up and 132 out of 256 (53%) have completed the 12-month follow-up to date, which is still in progress. Among those who completed interviews, there was only 1-3% missing data on most major outcomes (delirium, basic ADL, and readmission). CONCLUSION: The BASIL study presents an innovative effort to advance the conceptualization and measurement of delirium severity. Unique strengths include the diverse cohort with complete high quality data and longitudinal follow-up, along with detailed collection of multiple delirium measures daily during hospitalization.