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Supplementary Figure S1. CONSORT flow diagram for patient selection

Patient characteristics

Ipilimumab is effective for patients with melanoma, but not for those with less immunogenic tumors. We report a phase II trial of ipilimumab with concurrent or sequential stereotactic ablative radiotherapy to metastatic lesions in the liver or lung (NCT02239900). Ipilimumab (every 3 weeks for 4 doses) was given with radiotherapy begun during the first dose (concurrent) or 1 week after the second dose (sequential) and delivered as 50 Gy in 4 fractions or 60 Gy in 10 fractions to metastatic liver or lung lesions. In total, 106 patients received ≥1 cycle of ipilimumab with radiation. Median follow-up was 10.5 months. Median progression-free survival time was 2.9 months (95% confidence interval, 2.45–3.40), and median overall survival time was not reached. Rates of clinical benefit of nonirradiated tumor volume were 26% overall, 28% for sequential versus 20% for concurrent therapy (P = 0.250), and 31% for lung versus 14% for liver metastases (P = 0.061). The sequential lung group had the highest rate of clinical benefit at 42%. There were no differences in treatment-related adverse events between groups. Exploratory analysis of nontargeted lesions revealed that lesions receiving low-dose radiation were more likely to respond than those that received no radiation (31% vs. 5%, P = 0.0091). This phase II trial of ipilimumab with stereotactic radiotherapy describes satisfactory outcomes and low toxicities, lending support to further investigation of combined-modality therapy for metastatic cancers.

Response Rates of Unirradiated Tumors by Target site and Histology

Hepatic lesions measured at baseline for patients with evaluable imaging

Radiation therapy (RT) of thoracic cancers may cause severe radiation dermatitis (RD), which impacts on the quality of a patient's life. Aim of this study was to analyze the incidence of acute RD and develop normal tissue complication probability (NTCP) models for severe RD in thoracic cancer patients treated with Intensity-Modulated RT (IMRT) or Passive Scattering Proton Therapy (PSPT). We analyzed 166 Non-Small-Cell Lung Cancer (NSCLC) patients prospectively treated at a single institution with IMRT (103 patients) or PSPT (63 patients). All patients were treated to a prescribed dose of 60 to 74 Gy in conventional daily fractionation with concurrent chemotherapy. RD was scored according to CTCAE v3 scoring system. For each patient, the epidermis structure (skin) was automatically defined by an in house developed segmentation algorithm. The absolute dose-surface histogram (DSH) of the skin were extracted and normalized using the Body Surface Area (BSA) index as scaling factor. Patient and treatment-related characteristics were analyzed. The Lyman-Kutcher-Burman (LKB) NTCP model recast for DSH and the multivariable logistic model were adopted. Models were internally validated by Leave-One-Out method. Model performance was evaluated by the area under the receiver operator characteristic curve, and calibration plot parameters. Fifteen of 166 (9%) patients developed severe dermatitis (grade 3). RT technique did not impact RD incidence. Total gross tumor volume (GTV) size was the only non dosimetric variable significantly correlated with severe RD (p = 0.027). Multivariable logistic modeling resulted in a single variable model including S 20Gy, the relative skin surface receiving more than 20 Gy (OR = 31.4). The cut off for S 20Gy was 1.1% of the BSA. LKB model parameters were TD50 = 9.5 Gy, m = 0.24, n = 0.62. Both NTCP models showed comparably high prediction and calibration performances. Despite skin toxicity has long been considered a potential limiting factor in the clinical use of PSPT, no significant differences in RD incidence was found between RT modalities. Once externally validated, the availability of NTCP models for prediction of severe RD may advance treatment planning optimization.

Background Rate smoothing, which is available in some pacemakers and implantable cardioverter defibrillators (ICDs), has been used to prevent Torsades de Pointes in patients with long QT syndrome. Its efficacy in general ventricular arrhythmia prevention has not been determined. Objectives The purpose of the Ventricular Arrhythmia Suppression Trial (VAST) was to prospectively investigate whether rate smoothing could significantly reduce the incidence of ventricular tachyarrhythmias in a large, broad population of patients with ICDs. Methods Five hundred sixty-nine patients were enrolled at 57 participating centers and implanted with a commercially available Guidant ICD. A single-blinded crossover design was used in which each patient was randomized at implant to one of two treatment sequences: either rate smoothing on (RS On) followed by rate smoothing off (RS Off), or RS Off followed by RS On. This mode sequence was randomly determined and assigned in a 1:1 fashion using randomized permuted blocks by site. Each mode was followed for 6 months. Programming of rate smoothing was prescribed as 12% Down and 12% Up for the duration of the RS On period. Results Of enrolled patients, 281 were randomized to RS Off followed by RS On, and 288 to RS On followed by RS Off. With RS On, 75 (23%) patients experienced a reduction in arrhythmias, 76 (23%) saw an increase in arrhythmias, and the remaining 176 (54%) had no difference. No significant difference ( P = .58) in frequency of arrhythmias with RS On vs RS Off was found. Conclusion Rate smoothing does not result in a reduction in ventricular arrhythmias in a heterogenous population of patients receiving ICDs.

Background: Unnecessary right ventricular (RV) pacing in patients with implantable cardioverter defibrillators (ICD) may adversely affect heart failure morbidity and total mortality. Inhibition of Unnecessary RV Pacing with AV Search Hysteresis in ICDs (INTRINSIC RV) is a prospective, multicenter, randomized trial evaluating outcomes in ICD recipients programmed to single-chamber pacing (VVI) versus dual-chamber (DDDR) pacing with AV search hysteresis (AVSH). Methods: Patients underwent ICD implant (for standard indications). The ICD was programmed to DDDR with AVSH regardless of any need for pacing. Rate-adaptive pacing was set at 60–130 ppm with dynamic AV delay from 200 to 90 ms. AVSH was programmed to search every 32 intervals and extend the AV delay by 50%. One week post-implant patients with ICDs were interrogated to assess the percentage of RV pacing with the expectation that most would have

Implantable cardioverter-defibrillators (ICDs) are unequivocally the treatment of choice for patients who have already experienced a near-fatal tachyarrhythmic event. Recently, studies have conclusively demonstrated that extending the benefits of ICD therapy to postinfarction patients with resultant left ventricular dysfunction results in dramatic additional lifesaving without the need for complex riskstratification procedures. The landmark Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) shows that patients with reduced left ventricular function (ejection fraction < 30%) 1 month after a myocardial infarction should receive an ICD to prevent sudden cardiac death.

PURPOSE: The inhibition of activated Ras combined with radiotherapy was identified as a potential method for radiosensitization. MATERIALS AND METHODS: Immunoblotting was used to control for prenylation inhibition of the respective Ras isoforms and for changes in activity of downstream proteins. Clonogenic assays with human and rodent tumour cell lines and transfected cell lines served for the testing of radiosensitivity. Xenograft tumours were treated with farnesyl transferase inhibitors and radiation and assayed for ex vivo plating efficiency, regrowth of tumours and EF5 staining for detection of hypoxia. Concurrent treatment with L-778,123 and radiotherapy was performed in non-small cell lung cancer (NSCLC) and head and neck cancer (HNC) patients. RESULTS: Blocking the prenylation of Ras proteins in cell lines with Ras activated by mutations or receptor signalling resulted in radiation sensitization in in vitro and in vivo. The PI3 kinase downstream pathway was identified as a contributor to Ras-mediated radiation resistance. Additionally, increased oxygenation of xenograft tumours was observed after FTI treatment. Combined treatment in a phase I study was safe and effective in NSCLC and HNC. CONCLUSIONS: Tumour cells with activated Ras were sensitized to radiation. Unravelling the underlying mechanisms promises to lead to even more specific drugs with higher potency and safety.

This study investigated the demographic and clinical predictors of psychiatric hospitalization during the first 2 years of treatment for adults participating in the full-service partnership (FSP) program, based on Assertive Community Treatment, in a large county in northern California. Clinical and demographic characteristics, data on prior hospitalizations, length of enrollment, and living situation for 328 FSP participants were collected from the county’s internal billing system and the California Department of Health Care Services. In univariate models, the probability of hospitalization varied by diagnosis, age, and hospitalization history. In the multivariate model, younger age and frequent hospitalization prior to enrollment predicted hospitalization during enrollment. Findings support prior research on hospital recidivism and may be beneficial in refining future strategies for meeting the needs of adults with serious mental illness.

IMPACT (Improving Mood--Promoting Access to Collaborative Treatment) has a large body of evidence demonstrating its effectiveness for treating late-life depression in clients enrolled in a clinical research study, but little is known about how well the collaborative care model translates into treatment provided in a public mental health setting. This evaluation examines the influence of clinical and demographic characteristics in 112 older adults treated for late-life depression through publicly funded IMPACT in a large San Francisco Bay Area county. Depression severity decreased for 85% of clients between enrollment and treatments' end and 46% of clients realized a 50% reduction in symptom severity. Depression severity at enrollment, number of treatment sessions attended, ethnicity, and gender reliably predicted depression severity at the end of treatment. Men, clients attending more therapy sessions, and clients without substance abuse diagnoses had an increased likelihood of realizing a 50% reduction in symptoms. Results highlight the success of this evidence-based treatment program offered through the public mental health system but suggest that the demographic and clinical characteristics of the population being treated must be considered when adopting evidence-based practices.

There has been increasing interest in using of web-based surveys—rather than paper based surveys--for collecting data on alcohol and other drug use in middle and high schools in the US. However, prior research has indicated that respondent confidentiality is an underlying concern with online data collection especially when computer-assisted surveys are administered in group settings such as computer labs and classrooms. Using a sample of 341 high school students, we conducted a study comparing alcohol risk behavior prevalence rates from the web-based surveys with paper-form version of the same survey. The online surveys used in the study implemented several programming safeguards to enhance privacy. The goal of our study was to see if the risk-behavior items—when transitioned to an online format with these additional safeguards—would provide prevalence estimates that are comparable to its paper form version. Results showed that overall alcohol prevalence rates did not vary significantly between the two conditions. However, there was a significant interaction between gender and survey mode. Females reported lower mean risk indicator rates compared to males, possibly indicating stronger privacy concerns among the former group. The results suggest that online survey administration may require targeted efforts to help alleviate confidentiality concerns among adolescent girls.

Objectives The purpose of this study was to analyze defibrillation conversion data from the Low Energy Safety Study (LESS) to determine how implant criteria that use fewer inductions of ventricular fibrillation (VF) correlate with outcome and, in particular, to assess the reliability of using a single VF induction and test shock at 14 J. Background A safety margin of 10 J has become standard for implantation of an implantable cardioverter-defibrillator (ICD), but the specifics and rigor of the implant test sequence are not standardized. Methods In LESS, 611 ICD recipients completed a rigorous VF induction test scheme that began at 14 J and continued until the energy that succeeded three times without a failure was determined (DFT++). The data were analyzed to determine how well the outcome of the first 14-J shock and various other combinations of first and/or second shocks predicted a rigorous gold standard of DFT++ ≤21 J (i.e., three successes at ≤21 J). Results The positive predictive accuracy for the 91% of patients in whom the first 14-J shock succeeded was virtually identical to the positive predictive accuracy for the commonly used criteria of two successes at ≤17 J (99.1% vs 99.0%, P = .69), and slightly higher than the positive predictive accuracy for two successes at ≤21 J (98.8%, P = .51). A single success at 17 J or 21 J had a somewhat lower positive predictive accuracy of 98.2% ( P = .17). Eliminating VF induction testing would have resulted in a significantly lower positive predictive accuracy of 97.1% ( P = .01). Conclusions A single conversion success at 14 J on the first VF induction provides similar positive predictive accuracy as two successes at 17 J or 21 J. Using this criterion, 91% of patients meet implant criteria with a single induction of ventricular fibrillation.

The cryptophycin analogue LY355703 is a potent inhibitor of microtubule polymerization that displays in vitro and in vivo activity in cell lines and tumor xenografts displaying the multidrug-resistant phenotype. In a Phase I trial, 25 patients received LY355703 as a 2-h i.v. infusion on day 1 and day 8 repeated every 3 weeks. Doses were escalated from 0.1 to 2.22 mg/m2 using a modified continual reassessment method. Neurological toxicity was found to be dose-limiting at 1.84 and 2.22 mg/m2. Among four patients treated at these doses, two had grade 4 constipation/ileus, one with severe myalgias, and one had grade 3 motor neuropathy. These findings were reversible. The 1.5 mg/m2 dose level was well tolerated. An amended twice-weekly schedule was pursued in 11 patients in an attempt to improve dose intensity and avoid dose-limiting neurotoxicity. Doses of0.75 mg/m2 on a day 1, 4, 8, and 11 schedule every 21 days were not tolerated as a result of nausea/constipation, suggesting that LY335703 toxicity is not schedule dependent and is related to cumulative dose. LY355703 plasma concentrations measured by liquid chromatography with tandem mass spectrometry were evaluated using a population pharmacokinetic model. LY355703 was eliminated rapidly with a short terminal half-life that ranged from 0.8 to 3.9 h. Interpatient variability with respect to plasma clearance and volume of distribution, including covariates, was moderate at 32% and 39%, respectively. Maximum plasma concentration and area under the plasma concentration-time curve were linear over the dose range studied. A patient with non-small cell lung cancer previously treated with taxanes experienced a partial response lasting 4 months, and five patients had stable disease lastingor =3 months. LY355703 at a dose of 1.5 mg/m2 is recommended for Phase II evaluation on a days 1 and 8 schedule. Twice-weekly dosing did not allow improvement in dose intensity or tolerability.

This study investigated the safety and feasibility of transvenous biventricular defibrillation in ICD patients. Some patients may have high DFTs due to weak shock field intensity on the LV. Animal studies showed a LV shocking electrode dramatically lowered DFTs. This approach might benefit heart failure patients already receiving a LV lead or conventional ICD patients with high DFTs. A modified guidewire was used as a temporary left venous access defibrillation electrode (LVA lead). In 24 patients receiving an ICD, the LVA lead was advanced through a guide catheter in the coronary sinus (CS) and into a randomized LV vein (anterior or posterior) using a venogram for guidance. Paired DFT testing compared a standard right ventricular defibrillation system to a biventricular defibrillation system. There were no complications or adverse events. As randomized, LVA lead insertion success was 87% and 71% for anterior and posterior veins, respectively, and 100% after crossover. Total insertion process time included venogram time (32.5 +/- 26.9 minutes, range 5-115, mode 15 minutes) and LVA lead insertion time (15 +/- 14 minutes, range 1-51, mode 7 minutes). An apical LVA lead position was achieved in 11 (45%) of 24 patients and 7 (64 %) of these 11 displayed a DFT reduction; however, mean DFTs were not statistically different. Transvenous biventricular defibrillation is feasible and was safe under the conditions tested. Additional clinical studies are justified to determine if optimized LV lead designs, lead placement, and shock configurations can yield the same large DFT reductions as observed in animals.

This study examines the contribution of judge characteristics (sex-role identity as defined by the Bern Sex-Role Inventory [BSRI]) and of target characteristics (target gender and sex-typedness) to the social perception process. Subjects classified as feminine, masculine, androgynous, and undifferentiated performed two tasks. In the first, they read stories describing hypothetical stimulus persons. Next they were presented with feminine, masculine, and neutral traits, and were asked to decide whether or not they would use each trait to describe each target. Response times (RTs) and responses were recorded. In the second task, subjects were asked whether they would use sex-role-related traits to describe four different targets. These targets were famous people who varied in gender and sex-typedness. In the two tasks, there were strong and predictable effects due to target gender and target sex-typedness, both in the RTs and in the proportion of items ascribed to the target. For RTs, there were no effects d...

In an old creation myth, the androgyne stretches out and folds over itself to create a void in which the universe is born. This image is illuminating when one reflects on the poetic endeavor of Allen Ginsberg during the last thirty years. When the poet speaks of the “poem of life butchered out of their own bodies,” as he does in “Howl,” he signifies something about the creative effort expended in his own poetry and about the struggle of self to articulate a “true philosophy of life.” The ambiguity of the phrase “poem of life” is instructive as well, for it indicates a commitment to art and life as mutually informing categories. As the struggle for articulation is the struggle of the self to assert—or discover in the sense of revealing—its being in the world, the writing of poetry becomes a mode of self-creation. It becomes, in the terminology of existentialism, a “life project.”