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Primary spinal cord tumors are rare, particularly in the adult population, and national guidelines remain ambiguous with regard to management approaches. To address this knowledge gap, we evaluated management, outcomes, and prognostic factors of these neoplasms.The National Cancer Database was queried (2004-2016) for newly-diagnosed, histologically-confirmed WHO grades I-III astrocytomas and glioblastoma. Statistics included Kaplan-Meier overall survival (OS) analysis, along with Cox proportional hazards modeling.Of 1,033 subjects, 196 (19%) were pilocytic astrocytomas (PAs), 539 (52%) were grade II/III astrocytomas, and 298 (29%) were glioblastomas (GBMs). Respectively, 11%, 30%, and 27% did not undergo resection (biopsy only). RT was delivered to 27%, 54%, and 73%; chemotherapy was given to 5%, 21%, and 37%, respectively. The median OS was not reached for PAs, but was 101.2 months for grade II/III astrocytomas, and 23.9 months for GBMs (p 0.001). Neither chemotherapy nor RT (or dose thereof) was associated with increased OS for grade II/III astrocytomas (p 0.05 for all), though there was a trend toward improved OS with the use of chemotherapy for patients with GBM. Surgical resection was associated with improved OS for grade II/III astrocytomas and GBM (p 0.05). Independent prognostic factors for survival in this cohort included histologic classification and resection (compared to biopsy only) (p 0.05 for both).This study sheds light onto the management of these rare tumors; surgery was associated with OS benefit for patients with GBM and Grade II/III astrocytomas. Neither RT nor chemotherapy were associated with OS benefit. Although not implying causation, these data can be used to guide patient counseling and therapeutic approaches.

Metastatic cancer is a heterogeneous entity, some of which could benefit from local consolidative radiation therapy (RT). Although randomized evidence is growing in support of using RT for oligometastatic disease, a highly active area of investigation relates to whether RT could benefit patients with polymetastatic disease. This article highlights the preclinical and clinical rationale for using RT for polymetastatic disease, proposes an exploratory framework for selecting patients best suited for these types of treatments, and briefly reviews potential challenges. The goal of this hypothesis-generating review is to address personalized multimodality systemic treatment for patients with metastatic cancer. The rationale for using high-dose RT is primarily for local control and immune activation in either oligometastatic or polymetastatic disease. However, the primary application of low-dose RT is to activate distinct antitumor immune pathways and modulate the tumor stroma in efforts to better facilitate T cell infiltration. We explore clinical cases involving high- and low-dose RT to demonstrate the potential efficacy of such treatment. We then group patients by extent of disease burden to implement high- and/or low-dose RT. Patients with low-volume disease may receive high-dose RT to all sites as part of an oligometastatic paradigm. Subjects with high-volume disease (for whom standard of care remains palliative RT only) could be treated with a combination of high-dose RT to a few sites for immune activation, while receiving low-dose RT to several remaining lesions to enhance systemic responses from high-dose RT and immunotherapy. We further discuss how emerging but speculative concepts such as immune function may be integrated into this approach and examine therapies currently under investigation that may help address immune deficiencies. The review concludes by addressing challenges in using RT for polymetastatic disease, such as concerns about treatment planning workflows, treatment times, dose constraints for multiple-isocenter treatments, and economic considerations.

We addressed the prognostic impact of cell-of-origin (COO), MYC and Bcl-2 overexpression as well as isolated MYC rearrangement among 111 patients with limited stage diffuse large B-cell lymphoma (D...

BACKGROUND: Our previous dosimetric study showed that for locally advanced non-small cell lung cancer (LA-NSCLC), radiotherapy with intensity-modulated radiotherapy (IMRT) technique could deliver sufficient dose coverage to subclinical regions and reduce the dose to normal tissues with the omission of clinical target volume (CTV). To further clinically validate this strategy, we conducted the current study to analyze the failure pattern for patients with LA-NSCLC treated with concurrent chemotherapy and CTV-omitted IMRT. We also investigated the effects of target volumes on lymphopenia during radiotherapy to further test the potential benefits of CTV omission in anti-tumor immunotherapy. METHODS: A total of 63 patients with LA-NSCLC treated with CTV-omitted IMRT with concurrent chemotherapy were enrolled in this study. Their planning target volume (PTV) (also PTV-g) was expanded directly from gross tumor volume (GTV). A virtual CTV was expanded from GTV, and the PTV generated from virtual CTV was named planning target volume with CTV expansion (PTV-c). Treatment failures were divided into local, regional, and distant failures, and local–regional recurrences were classified into inside PTV-g (IN-PTV-g), between PTV-g and PTV-c (PTV-g-c), and outside PTV-c (OUT-PTV-c). The relationship between lymphopenia during radiotherapy and the target volumes was also evaluated using Spearman’s correlation analysis. RESULTS: Among the 60 patients with detailed follow-up data for recurrences, 46 (76.7%) experienced recurrences, with 18 (30.0%) being local recurrence, 5 (8.4%) being regional failure, and 33 (55.0%) being distant failure. For the 21 patients with local–regional recurrences, 16, 6, and 1 were IN-PTV-g, OUT-PTV-c, and PTV-g-c recurrences, respectively. Lymphopenia during radiotherapy was associated with both GTV and PTV, with larger volumes linked to severe lymphopenia. CONCLUSIONS: CTV omission is feasible for LA-NSCLC treated with concurrent chemoradiotherapy and does not compromise failure inside the subclinical region. The radiation volumes were associated with lymphopenia during radiotherapy, with larger volumes related to severe lymphopenia. This finding supports the further exploration of CTV omission for immunotherapy.

Pristine and Mn-doped bismuth ferrite samples were prepared by sol–gel method. XRD patterns showed rhombohedral to orthorhombic phase transition with Mn doping in BiFeO3 sample. The surface morphology of the samples was carried out by scanning electron microscope which exhibited a decrease in grain size with Mn doping. Magnetic hysteresis curves exhibit that manganese doping induces modification in magnetic properties of bismuth ferrites. Significant modification was observed in dielectric with Mn doping and maximum value was recorded for BiFe0.8Mn0.20O3 sample. P–E hysteresis curves were recorded to evaluate the ferroelectric properties of all samples at room temperature. A significant improvement was observed in ferroelectric properties in doped samples. Bandgap values of BiFe1−xMnxO3 in UV–Vis region decreases with Mn doping and minimum for BiFe0.80Mn0.20O3 sample as evaluated from Tauc’s plots. I–V studies of pristine and Mn-doped samples were carried out with light and without light. Enhanced photocurrent density was observed in Mn-doped BFO samples. Hence, these modifications in ferroelectric and photovoltaic properties of BiFe1−xMnxO3 samples make bismuth ferrites a good candidate for photovoltaic applications.

PurposeThe purpose of this study is to examine the impact of financial and technical education of chief executive officer (CEO) on investment–cash flow sensitivity (ICFS) of Indian manufacturing firms.Design/methodology/approachThe study uses the dynamic panel data model and more specifically, the system-generalized method of moments (GMM) technique to investigate the effect of CEOs' education on ICFS of Indian manufacturing firms during the period 1998–1999 to 2016–2017.FindingsThe study shows that financial (technical) education of CEOs does (not) affect ICFS. The results explain that the role of the CEO's education in ICFS is highly significant during the crisis period. The robustness test depicts that the influence of financial education on ICFS is less (more) for group-affiliated and large-sized firms (stand-alone and small-sized firms). Further, the CEO's education is significantly associated with corporate investment decisions.Research limitations/implicationsDue to the unavailability of the CEO's compensation data for the selected sample, future research could explore the impact of CEO's education with respect to CEO's compensation on ICFS.Practical implicationsFirst, the authors find that financially educated CEOs affect ICFS; therefore, firms should take care of CEO's education during recruitment of CEOs. Second, lending agencies should also consider the educational background of the CEO before approval of funding to make it safe. Third, investors should keep in mind the educational background of the CEO for the growth of their investment as it may be easier for financially educated CEOs to borrow from the market at the time of requirement.Originality/valueThis study contributes to the existing literature by providing empirical evidence through analyzing the impact of a CEO's education on ICFS in the context of India. This study is very unique in itself as it uses the sample of manufacturing sectors of India, which are growing very fast and attracting global investors to create a global hub of manufacturing in India. This study also considers different types of education such as financial and technical education of CEOs in the context of a developing economy like India. This study made its findings robust across company characteristics and periods based on the financial crisis.

Phase 3 clinical trials are widely recognized as the highest level of evidence to support a particular intervention/therapy in the medical literature. The ability to draw clinically meaningful conc...

Fluorescent probes based on semiconducting polymer nanoparticles (NPs) such as polyaniline (PANI) usually require external fluorophore doping to provide fluorescence function. Direct use of PANI-based NPs for bioimaging applications has been limited by PANI's weak blue fluorescence and aggregation-induced quenching in physiological medium. In this report, we developed a facile solid-state synthesis method to produce fluorescent polyaniline nanoparticles (FPNs) that are not only water-soluble but also exhibit high intensity and pH-sensitive red fluorescence. The FPNs showed high photoluminescence quantum yield (PLQY) of 19.3 % at physiological pH, which makes FPNs ideal for application as fluorescent nanoprobes in bioimaging. Moreover, we performed an in-depth study of photoluminescence dependence on pH and the phenomena of exciton-polaron quenching at low pH was highlighted. We also found that the ratio of emission intensity at 600 nm and 650 nm increased from 0.04 to 1.65 as pH was raised from 2.6 to 11.8, which could find its application in ratiometric pH sensing. FPNs exhibited excellent biocompatibility with85 % cell viability for fibroblasts NIH/3 T3 and prostate cancer 22RV1 cells even at concentrations as high as 1000 μg/mL. In addition, fluorescence microscopy demonstrated concentration-dependent red fluorescence in the cytoplasm owing to the cellular uptake of FPNs in prostate cancer cells.

The successes of local therapy for oligometastatic cancers cannot be extrapolated to oligoprogressive disease (OPD) because they are distinct clinical entities. Given the limited prospective data on OPD to date, summative analyses are urgently needed.Inclusion criteria for this Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review were as follows. First, only prospective data were included. Second, progression had to have occurred on active/ongoing systemic therapy. Third, the number of progressing areas of disease had to be explicitly listed and ≤5 in number. Fourth, all progressing sites had to undergo local therapy (radiation therapy [RT] /surgery/nonradiation ablative procedures).Eight trials met criteria (summing 290 patients), the vast majority of which used stereotactic RT as the local modality (most commonly, 19-20 Gy in 1 fraction, 27-33 Gy in 3 fractions, or 35-50 Gy in 5 fractions). A study on non-small cell lung cancer (NSCLC) demonstrated that stereotactic RT improved progression-free survival (PFS) and overall survival compared with historical values with systemic therapy alone. Two additional studies on epidermal growth factor receptor mutated (EGFRm) NSCLC also showed acceptable PFS with local therapy, particularly in patients who oligoprogressed on osimertinib. The only randomized trial analyzed herein showed that local therapy improved PFS for NSCLC but not breast cancer. Two trials in castration-resistant prostate cancer illustrated that a substantial proportion of patients did not require any changes in hormonal therapy or delayed the need to change systemic therapies. Lastly, 2 trials of renal cell carcinoma showed high (90%-100%) local control and median PFS of 9 months, and potentially a prolonged time to change systemic therapy. Lastly, from all patients in all trials, local therapy was tolerated well, with only 7 instances of grade 3+ toxicities.Based on the limited data, local therapy for oligoprogression is safe and yields encouraging short-term preliminary outcomes, but trials with larger sample sizes and longer follow-up are required for more robust conclusions.

The transition from acute to chronic pain is critically important but not well understood. Here, we investigated the pathophysiological mechanisms underlying the transition from acute to chronic low back pain (LBP) and performed transcriptome-wide analysis in peripheral immune cells of 98 participants with acute LBP, followed for 3 months. Transcriptomic changes were compared between patients whose LBP was resolved at 3 months with those whose LBP persisted. We found thousands of dynamic transcriptional changes over 3 months in LBP participants with resolved pain but none in those with persistent pain. Transient neutrophil-driven up-regulation of inflammatory responses was protective against the transition to chronic pain. In mouse pain assays, early treatment with a steroid or nonsteroidal anti-inflammatory drug (NSAID) also led to prolonged pain despite being analgesic in the short term; such a prolongation was not observed with other analgesics. Depletion of neutrophils delayed resolution of pain in mice, whereas peripheral injection of neutrophils themselves, or S100A8/A9 proteins normally released by neutrophils, prevented the development of long-lasting pain induced by an anti-inflammatory drug. Analysis of pain trajectories of human subjects reporting acute back pain in the UK Biobank identified elevated risk of pain persistence for subjects taking NSAIDs. Thus, despite analgesic efficacy at early time points, the management of acute inflammation may be counterproductive for long-term outcomes of LBP sufferers.

Purpose Radiotherapy (RT) constitutes a mainstay in the treatment of elderly patients with head and neck cancer (HNC), but use of simultaneous chemoradiotherapy (CRT) remains controversial. We have conducted a prospective analysis based on real-world patient data to examine the health-related quality of life (HRQoL) and cost effectiveness (CE) of CRT vs. RT in elderly HNC patients. Methods Eligible participants ≥ 65 years treated in a large tertiary cancer center between July 2019 and February 2020 who completed the validated EQ-5D-5L questionnaire (health state index [HI] and visual analog scale [VAS]) before and after RT were included. CE referred to direct medical costs, including diagnosis-related group (DRG)-based billings for inpatients and uniform assessment standard (EBM)-based costs for outpatients. The primary endpoint was cost (euros [€]) per quality-adjusted life year (QALY). The incremental cost-effectiveness ratios (ICERs) were calculated. Costs and QALYs were not discounted for short overall survival (OS). Results Baseline HRQoL was 0.878 (±0.11) in the CRT group and 0.857 (±0.17) in the RT group. Upon completion of therapy, HRQoL amounted to 0.849 (±0.14) in the CRT and 0.850 (±0.13) in the RT group. The mean treatment-related cost in the CRT cohort was €22,180.17 (±8325.26) vs. €18,027.87 (±26,022.48) in the RT group. The corresponding QALYs amounted to 2.62 in the CRT and 1.91 in the RT groups. The ICER was €5848.31. Conclusion This is the first analysis from the German health care system demonstrating that the addition of chemotherapy to RT for selected elderly HNC patients is cost effective and not associated with a significant HRQoL decline.

Regenerative stem cell–like memory (T(SCM)) CD8(+) T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces T(SCM) that have naive phenotype with self-renewability, enhanced multipotency and proliferative capacity. This is achieved by delaying cell division and enhancing mitochondrial biogenesis and fatty acid oxidation, without affecting T cell receptor-mediated activation. DNA methylation profiling revealed that MEKi-induced T(SCM) cells exhibited plasticity and loci-specific profiles similar to bona fide T(SCM) isolated from healthy donors, with intermediate characteristics compared to naive and central memory T cells. Ex vivo, antigenic rechallenge of MEKi-treated CD8(+) T cells showed stronger recall responses. This strategy generated T cells with higher efficacy for adoptive cell therapy. Moreover, MEKi treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects. In conclusion, we show that MEKi leads to CD8(+) T cell reprogramming into T(SCM) that acts as a reservoir for effector T cells with potent therapeutic characteristics.

Recently, it has been observed that few drops of water on the surface of oxide materials can generate electricity which is eco-friendly and cost effective. This hydroelectric cell (HEC) may serve as an unconventional source of electrical energy. HEC production cast is very low. Porous SnO2 samples for hydroelectric cell have been prepared by solid-state sintering method. Phase formation and structural analysis of the sample was confirmed by X-ray diffraction pattern using Rietveld analysis. The surface morphology of the sample was determined using field emission scanning electron microscopy. Average grain size of porous sample was depicted 65 nm using image j software. The pore size distribution and specific surface area of SnO2 nanoparticles were examined by the Barrett–Joyner–Halenda technique. A circular pellet having diameter of 2 inch and a square pellet having a side of 2 cm was prepared to study the hydroelectric properties. Peak current value 72.1 mA was observed in circular pellet with almost constant voltage of 0.981 V whereas peak current and voltage values for the square pellet were 12.5 mA and 0.972 V respectively. Dissociation of water and conduction phenomenon have been confirmed using dielectric and DC conductivity behavior of samples.

The crystal growth kinetics of piracetam, fenofibrate, phenylbutazone, acetaminophen, carbamazepine, and risperidone in methanol have been studied by two different methods; the isothermal seeded de...

Background Despite accounting for a minority of malignant pleural mesothelioma (MPM) diagnoses, females may experience differential survival relative to males. It is unclear if there are gender-based differences in receipt of treatment or disease-related outcomes for patients with MPM. We therefore utilized the National Cancer Database (NCDB) to assess patterns-of-care and overall survival (OS) among patients with MPM by gender. Materials and Methods Patients with histologically confirmed MPM treated from 2004 to 2013 were identified from the NCDB. The association between female gender and OS was assessed using multivariable Cox proportional hazards models with propensity score matching. Patterns-of-care were assessed using multivariable logistic regression. The overall treatment effect was tested in subsets of patients by treatment strategy, histology, and clinical stage. Results A total of 18,799 patients were identified, of whom 14,728 (78%) were male and 4071 (22%) were female. Females were statistically more likely to present at a younger age, with fewer comorbidities, and with epithelioid histology. Despite these favorable prognostic features, women were less likely to receive surgery (P ≤ .001) or chemotherapy (P ≤ .001) compared with males. On multivariable analysis, female gender was associated with improved OS (hazard ratio, 0.83; 95% confidence interval, 0.80-0.86; P ≤ .001). Gender-based survival differences were seen across all stages, but only among patients with epithelioid (P ≤ .001) and not biphasic (P = .17) or sarcomatoid (P = 1.00) histology. Conclusions Surgery and chemotherapy are disproportionately underutilized in female patients with MPM. Despite this concerning disparity, female gender is independently associated with improved survival relative to males. Further research to understand factors that lead to gender disparities in MPM is warranted.

In order to form a solid solution with its prodrug cortisone, hydrocortisone (cortisol) must violate Etter’s rule of hydrogen bonding. The preparation of a uniform product with the desired composition, which is hindered under a thermodynamic regime, can be achieved by supercritical assisted spray drying. The new phase enables fine-tuning of the phase’s composition as well as a higher dissolution rate for hydrocortisone., Multidrug products enable more effective therapies and simpler administration regimens, provided that a stable formulation is prepared, with the desired composition. In this view, solid solutions have the advantage of combining the stability of a single crystalline phase with the potential of stoichiometry variation of a mixture. Here a drug–prodrug solid solution of cortisone and cortisol (hydrocortisone) is described. Despite the structural differences of the two components, the new phase is obtained both from solution and by supercritical CO2 assisted spray drying. In particular, to enter the solid solution, hydrocortisone must violate Etter’s rules for hydrogen bonding. As a result, its dissolution rate is almost doubled.

The management of stage III non-small cell lung cancer (NSCLC) remains complex and controversial, with a myriad of potentially feasible options. Given the diversity of non-surgical as well as surgical options, along with recent randomized data regarding adjuvant immunotherapy that has re-defined the standard of care for unresected stage III NSCLC cases, the goal of this narrative review was to provide a contemporary view at how management of these patients can be further optimized. Topics discussed include the following items: optimizing toxicity mitigation strategies (in order to avoid impaired receipt of subsequent therapies), the importance of multidisciplinary tumor boards (MTBs) and multidisciplinary clinics (MDCs), adhering to treatment approaches endorsed by national guidelines, prudently selecting patients for surgical intervention (as compared to non-operative approaches), coordination of multidisciplinary care so as to best preserve all potential therapeutic options, and addressing challenges regarding disparities in access to oncologic care. This review places particular emphasis for community and/or rural centers, which may not have the same level of resources and/or personnel as larger academic institutions. Taken together, these strategies are aimed towards the overarching goal of streamlining oncologic care for stage III NSCLC cases in light of the numerous approaches that currently exist for these patients.

Background The use of professional medical writers (PMWs) has been historically low, but contemporary data regarding PMW usage are scarce. In this study, we sought to quantify PMW use in oncologic phase III randomized controlled trials (RCTs). Methods We performed a database query through ClinicalTrials.gov to identify cancer‐specific phase III RCTs; we then identified whether a PMW was involved in writing the associated trial manuscript reporting primary endpoint results. Results Two‐hundred sixty trials of 600 (43.3%) used a PMW. Industry‐funded trials used PMWs more often than nonindustry trials (54.9% vs. 3.0%, p < .001). Increased PMW usage was further noted among trials meeting their primary endpoint (53.4% vs. 32.9%, p < .001) and trials that led to subsequent Food and Drug Administration approval (63.1% vs. 36.3%, p < .001). By treatment interventions, PMW use was highest among systemic therapy trials (50.2%). Lastly, the use of PMWs increased significantly over time (odds ratio: 1.11/year, p = .001). Conclusion PMW use rates are high among industry‐funded trials. We urge continued and increased transparency in reporting the funding and use of PMWs., Considering the increase in industry‐sponsored cancer clinical trials, the use of professional medical writers for publication of trial results has become an increasingly important topic. This brief communication reports the current rate of involvement of medical writers in publications of cancer clinical trials.

Immune function (e.g. absolute lymphocyte count (ALC)) and modifiable predictors thereof (e.g. volume of the heart/lungs receiving low-dose radiation) impact outcomes of cancer patients, but this has not been well-studied in the immunotherapy era. This investigation of metastatic lung cancer assessed the interaction of dosimetric parameters (e.g. lung/heart V5), radiotherapy technique (e.g. stereotactic (SBRT) or traditional radiotherapy), lymphopenia, and survival outcomes.Patients were collected from three institutional phase I/II trials of combined immunotherapy and lung irradiation. SBRT referred to 50 Gy/4 fractions or 60 Gy/10 fractions, and traditional RT as 45 Gy/15 fractions. Blood collections were standardized on the first and last day of radiotherapy and each cycle of immunotherapy. Statistics included multivariable linear regression to identify variables associated with ALC decline, Kaplan-Meier analysis of overall and progression-free survival (PFS), and Cox multivariate analysis.The median follow-up of the 165 patients was 21 months. The only factor independently predictive of ALC decline was traditional RT (p 0.001). Therefore, the analysis was repeated for traditional RT and SBRT separately; lung V5 was associated with lymphopenia for traditional RT (p 0.001) but not SBRT (p = 0.12). Pre-radiotherapy ALC was independently associated with PFS in both cohorts (p 0.05 for both); post-RT ALC predicted for PFS in the traditional RT (p = 0.048) but not the SBRT (p = 0.90) group. Neither heart nor lung V5 was independently associated with PFS.When combined with immunotherapy, SBRT may better preserve lymphocytes (and hence improve outcomes) than traditional RT. When administering traditional RT, constraining the lung V5 may indirectly impact outcomes by means of ALC preservation.

Purpose Management options for localized prostate cancer include definitive radiation therapy (RT) or radical prostatectomy, with a subset of surgical patients requiring adjuvant or salvage RT after prostatectomy. The use of a peri-rectal hydrogel spacer in patients receiving definitive RT has been shown to reduce rectal doses and toxicity. However, in the postprostatectomy setting, a hydrogel spacer cannot be routinely placed. Therefore, we sought to compare rectal dosimetry between definitive RT with a hydrogel spacer versus postoperative RT. Methods and Materials We identified patients with prostate cancer who underwent conventionally fractionated RT. Rectal dosimetry was evaluated between 2 groups: definitive RT with a hydrogel spacer (79.2 Gy, group 1) and postoperative RT (70.2 Gy, group 2). Rectal dosimetry values were tabulated and compared using Mann-Whitney U test. We implemented a Bonferroni correction to account for multiple comparisons (threshold P < .005). Linear regression analysis evaluated predictors of candidate rectal dose-volume parameters. Results We identified 51 patients treated during years 2017 to 2018; 16 (31%) and 35 (69%) patients were included in groups 1 and 2, respectively. The rectal volume receiving ≥65 Gy (V65) was significantly lower in group 1 (median, 2.1%; interquartile range, 0.9%-3.1%) than in group 2 (10.7%, 6.6%-14.5%) (P < .001). Use of a hydrogel spacer in the definitive setting was independently associated with lower V65 (P < .001). Similar results were found for V60, V55, V50, and V45 (P < .005 for all). Conclusions Rectal dosimetry is more favorable for definitive RT (79.2 Gy) with a hydrogel spacer compared with postoperative RT (70.2 or 66.6 Gy). This may inform shared decision-making regarding primary management of prostate cancer, especially among patients at high risk of needing postoperative RT after prostatectomy.

Rechargeable Al-ion aqueous batteries (AIABs) are emerging contenders for massive battery systems due to economic, abundance, environmental, and safety advantages. However, the high capacity of metallic-Al remains untapped due to native oxide barrier formation. Engineering oxide removal by treating Al metal with an ionic liquid mixture solves this problem but the role of this treated-Al (TAl) in influencing full-cell battery performance is not yet fully understood. At the same time, the stability and compatibility of the coating layer applied on Al metal remain unexplored for long-term handling in full-cell assembly lines. Here, we explore the above two aspects of TAl in the context of a full-cell AIAB. First, a highly stable cathode material, NMnHCF, is demonstrated to successfully store an Al-ion by reversibly transforming from the monoclinic to tetragonal phase. A high energy density surpassing previous equivalent reports has been reported. Second, it is revealed that combinations of electrolyte–TAl pairings significantly influence the overall battery performance, wherein electrolyte conductivity influences the Al plating/stripping overpotential, which in turn dictates the overall battery performance. We also document that chlorinated coatings on TAl are stable under ambient atmosphere for at least 40 h and prevent reoxidation of the bulk aluminum metal during battery fabrication and electrochemical cycling National Research Foundation (NRF) Accepted version This work was financially supported by the National Research Foundation of Singapore (NRF) Investigatorship Award Number NRFI2017-08/NRF2016NRF-NRFI001-22.

Purpose Clinical trials are considered the gold standard in evidence-based medicine, yet few patients with cancer ultimately enroll. Here we examine patients screened for thoracic radiation oncology clinical trials to better understand enrollment trends. Methods and Materials A prospective database tracking screening and enrollment for patients referred for thoracic radiation oncology consultation at our institution from 2016 to 2019 was evaluated. Proportional enrollment rates, patient and disease characteristics, self-reported socioeconomic factors, and reasons for ineligibility or nonenrollment across 17 radiation therapy trials were compared. Results Enrollment data on 2372 patients were available for analysis. Of these patients, 40.0% (949) were deemed “not eligible” (NE) for any trial or were unwilling to be further screened. Reasons for ineligibility included stage (44%), histology (13%), radiation therapy not indicated (12%), patient decision (7%), and enrollment in a competing medical or surgical oncology trial (5%). The remaining 60.0% (1423) were “potentially eligible” (PE) for one or more trials. Most had non-small cell lung cancer (71%) or esophageal cancer (16%), and there were significantly fewer stage IV PE (29%) versus NE (49%) patients (P Conclusions Only 12% of patients screened for radiation therapy trials ultimately enrolled, and more than two-thirds had no trial available or were found ineligible. In addition, 19% of potential eligible patients did not enroll because the patient or physician declined. Future trials may benefit from pragmatic designs with more inclusive enrollment criteria and multidisciplinary engagement of referring providers.

The optimal tumor-free margin definition and width following breast-conserving therapy (BCT) for early-stage invasive cancers has been evaluated in previous meta-analyses and guidelines. We performed an updated meta-analysis to assess how improvements in treatment over time have affected the impact of margins on local recurrence (LR) rates over time. A systematic literature review identified 38 eligible studies comprising 54,502 patients treated between 1968 and 2010. Inclusion criteria included patients treated with BCT and minimum follow-up of 50 months, pathologic definitions of margin status explicitly stated, and LR data in relation to margin status. Data were pooled using a Bayesian logistic regression model to evaluate the risk of LR in relation to both margin status and study enrollment periods. Median follow-up was 7.25 years. Absolute LR rates decreased over time for each margin width cohort, with maximum differences between negative margin groups of less than 1% for the most recent enrollment period. However, relative rates of LR between different margin groups remained stable over time. With an additional 22,000 patients compared with the previous meta-analysis, this updated meta-analysis supports the consensus guideline of “no tumor on ink” for the majority of patients. Additionally, while concerns exist regarding a benefit with wider margins from previous studies, the analysis demonstrates the impact of margin width on LR rates has declined substantially over time, with very small differences between the narrowest and widest margin groups in the most recent cohort. Hence, older studies appear to have limited value to inform current management guidelines.

Alterations in cellular energy metabolism have been implicated in chronic pain, suggesting a role for mitochondrial DNA. Previous studies reported associations of a limited number of mitochondrial DNA polymorphisms with specific pain conditions. In this study, we examined the full mitochondrial genomes of people with a variety of chronic pain conditions. A discovery cohort consisting of 609 participants either with or without a complex persistent pain conditions (CPPCs) was examined. Mitochondrial DNA was subjected to deep sequencing for identification of rare mutations, common variants, haplogroups, and heteroplasmy associated with 5 CPPCs: episodic migraine, irritable bowel syndrome, fibromyalgia, vulvar vestibulitis, or temporomandibular disorders. The strongest association found was the presence of the C allele at the single nucleotide polymorphism m.2352T>C (rs28358579) that significantly increased the risk for fibromyalgia (odds ratio [OR] = 4.6, P = 4.3 × 10). This relationship was even stronger in women (OR = 5.1, P = 2.8 × 10), and m.2352T>C was associated with all other CPPCs in a consistent risk-increasing fashion. This finding was replicated in another cohort (OR = 4.3, P = 2.6 × 10) of the Orofacial Pain: Prospective Evaluation and Risk Assessment study consisting of 1754 female participants. To gain insight into the cellular consequences of the associated genetic variability, we conducted an assay testing metabolic reprogramming in human cell lines with defined genotypes. The minor allele C was associated with decreased mitochondrial membrane potential under conditions where oxidative phosphorylation is required, indicating a role of oxidative phosphorylation in pathophysiology of chronic pain. Our results suggest that cellular energy metabolism, modulated by m.2352T>C, contributes to fibromyalgia and possibly other chronic pain conditions.

Lymph node (LN) involvement is a poor prognostic factor for malignant pleural mesothelioma (MPM). However, to our knowledge, postresection outcomes of node-negative (cN0/pN0), occult pathologic nodal disease (cN0/pN+), and clinical node-positive disease (cN+) have not been compared to date.The National Cancer Data Base was queried for newly diagnosed, resected MPM with known clinical/pathologic LN information. Three cohorts were compared: cN0/pN0, cN+, and cN0/pN+. Multivariable logistic regression examined predictors of pathologic nodal upstaging. Kaplan-Meier analysis with propensity matching assessed overall survival (OS); multivariate Cox proportional hazards modeling examined predictors thereof.Of 1369 patients, 687 (50%) had cN0/pN0, 457 (33%) cN+, and 225 (16%) cN0/pN+ disease. Median follow-up was 29 months. In patients with cN0 disease, factors associated with pathologic nodal upstaging were younger age, greater number of examined LNs, and nonsarcomatoid histology (P .05 for all). Relative to pN0 cases, occult LN involvement (65% being pN2) was associated with 51% higher hazard of mortality on multivariate analysis (P = .005). Following propensity matching, the OS of cN0/pN+ was similar to cN+ cases (P = .281). On multivariate analysis, the number of involved LNs (continuous variable, P = .013), but not nodal tumor, node, metastasis (TNM) classification or LN ratio (P.05 for both), was associated with OS.Detecting occult nodal disease during resection for cN0 MPM is associated with poorer prognosis, with similar survival as cN+ cases, underscoring the importance of routine preoperative pathologic nodal assessment for potentially resectable MPM. The number of involved LNs (rather than current location-based classification) may provide more robust prognostic stratification for future TNM staging.

Immune checkpoint inhibitors, such as anti–PD-1/PD-L1, have emerged as promising therapies for advanced non–small cell lung cancer (NSCLC). However, approximately 80% of patients do not respond to immunotherapy given alone because of intrinsic or acquired resistance. Radiotherapy (XRT) can overcome PD-1 resistance and improve treatment outcomes, but its efficacy remains suboptimal. The tyrosine phosphatase SHP-2, expressed in some cancers and in immune cells, has been shown to negatively affect antitumor immunity. Our hypothesis was that SHP-2 inhibition in combination with anti–PD-L1 would enhance immune-mediated responses to XRT and synergistically boost antitumor effects in an anti–PD-1–resistant mouse model. We treated 129Sv/Ev mice with anti–PD-1–resistant 344SQ NSCLC adenocarcinoma with oral SHP099 (a SHP-2 inhibitor) combined with XRT and intraperitoneal anti–PD-L1. Primary tumors were treated with XRT (three fractions of 12 Gy each), whereas abscopal (out-of-field) tumors were observed but not treated. XRT in combination with SHP099 and anti–PD-L1 promoted local and abscopal responses, reduced lung metastases, and improved mouse survival. XRT also increased SHP-2+ M1 tumor-associated macrophages in abscopal tumors (P = 0.019). The addition of SHP099 also associated with a higher M1/M2 ratio, greater numbers of CD8+ T cells, and fewer regulatory T cells. This triple-combination therapy had strong antitumor effects in a mouse model of anti–PD-1–resistant NSCLC and may be a novel therapeutic approach for anti–PD-1–resistant NSCLC in patients.

Hemolysin expressing UPEC strains have been associated with severe advanced kidney pathologies, such as cystitis and pyelonephritis, which are associated with an inflammatory response. Macrophages play an important role in regulating an inflammatory response during a urinary tract infection. We have studied the role of purified recombinant α-hemolysin in inducing inflammatory responses and cell death in macrophages. Acylation at lysine residues through HlyC is known to activate proHlyA into a fully functional pore-forming toxin, HlyA. It was observed that active α-hemolysin (HlyA) induced cleavage of caspase-1 leading to the maturation of IL-1β, while inactive α-hemolysin (proHlyA) failed to do so in THP-1 derived macrophages. HlyA also promotes deubiquitination, oligomerization, and activation of the NLRP3 inflammasome, which was found to be dependent on potassium efflux. We have also observed the co-localization of NLRP3 within mitochondria during HlyA stimulations. Moreover, blocking of potassium efflux improved the mitochondrial health in addition to a decreased inflammatory response. Our study demonstrates that HlyA stimulation caused perturbance in potassium homeostasis, which led to the mitochondrial dysfunction followed by an acute inflammatory response, resulting in cell death. However, the repletion of intracellular potassium stores could avoid HlyA induced macrophage cell death. The findings of this study will help to understand the mechanism of α-hemolysin induced inflammatory response and cell death.

Purpose Adult medulloblastoma is rare, and management is extrapolated from pediatric cases. This investigation evaluated the prognostic role of chemotherapy (and sequencing thereof), the degree of resection, and craniospinal irradiation (CSI) dose. Methods The National Cancer Database was queried for adult (age ≥18) medulloblastoma. Resection was coded as gross (GTR) or subtotal resection (STR) or biopsy only; concurrent chemoradiotherapy (CRT) was defined as receipt within 14 days of each other. Statistics included Kaplan-Meier overall survival (OS) analysis and Cox proportional hazards modeling. Results Of 1144 patients, 613 had coded surgical information; 242 (39%) did not undergo surgery, 277 (45%) underwent STR, and 94 (15%) had GTR. A total of 428 (37.4%) did not receive chemotherapy, 348 (30.4%) received sequential CRT, and 368 (32.2%) underwent concurrent CRT. Of the 711 patients with CSI dose information, 202 (28.4%) received 23–30 Gy CSI and 509 (71.6%) patients received 30–36 Gy. Median follow-up was 56.5 months. Extent of resection did not correlate with 10-year OS (74.2% biopsy only, 72.7% STR, 82.2% GTR, p > 0.05 all comparisons) or on Cox multivariate analysis. Chemotherapy was associated with higher OS (65.6% vs. 51.2%, p = 0.035) and a trend towards significance on multivariate assessment (p = 0.082). Sequencing of chemotherapy and CSI dose were not associated with OS (p > 0.05 for both). Conclusions Although causation cannot be implied, neither the extent of resection nor CSI dose associated with OS in adult medulloblastoma. Chemotherapy could have utility in higher-risk patients; concurrent administration may not be beneficial, especially given therapy-induced neuro-cognitive sequelae.

In this study, we report a controlled one-pot green synthesis of multiwalled carbon nanotubes (MWCNTs) via pyrolysis of sustainable agriculture waste (chickpea peel) at 400 °C in aqueous medium. These MWCNTs demonstrated 7.0 nm diameter, 0.28 nm graphitic spacing with carbonyl, hydroxyl, and carboxylic acid functionality. The D band (presence of sp3 defects) and G band (E2g mode of graphite) at 1350 cm−1 and 1580 cm−1 originated in Raman spectrum, respectively. The prepared MWCNTs showed blue fluorescence with 10% fluorescence quantum yield in aqueous medium. The MWCNTs showed triple exponential decay characteristics with an average fluorescence lifetime of 4.7 ns. The synthesized MWCNTs revealed a consistent fluorescence in the cytoplasm of 22RV1 human prostate carcinoma cell line without exerting any sign of cytotoxicity. The MWCNTs also exhibited remarkable cytocompatibility in human immortalized prostate epithelial RWPE1 cells.

Background Radiotherapy (RT) can be used for tumor downstaging and as a bridge to transplantation in hepatocellular carcinoma (HCC), but its effect on surgical complications is unknown. Therefore, we investigated post-transplant mortality and acute readmission rates in HCC with and without preoperative RT using the National Cancer Database (NCDB). Methods After exclusion, 11,091 transplant patients were analyzed, 165 of whom received RT prior to transplant. Multivariable binomial logistic regression analysis identified characteristics associated with use of RT, and factors associated with increased 30/90-day mortality and 30-day readmission, following propensity matching. Results Although RT (median 40 Gy in 5 fractions) was more often delivered to larger tumors and advanced stages, it resulted in 59% downstaging rate, 39% pathologic complete response rate, and a median of 4 additional months to transplantation. Crude 30/90-day mortality rates were both 1.2% with preoperative RT, compared to 2.7% and 4.4% without. The 30-day readmission rate was 5.5% with RT and 10.7% without it. Propensity matched analysis demonstrated no statistical differences in 30/90-day mortality and a lower 30-day readmission rate with preoperative RT. Age >58, stage III disease, lack of transarterial chemoembolization, and shorter time to transplant independently predicted higher 90-day mortality. Conclusion Preoperative RT for HCC did not increase postoperative mortality or length of stay following liver transplant.

Introduction Even though the increasing incidence of VIM-producing E. coli and K. pneumoniae has been reported worldwide, studies are still lacking in Palestine. The aim of this study was to screen carbapenem-resistant E. coli and K. pneumoniae bacteria in the Gaza Strip, Palestine and further to characterize carbapenemase-producing isolates. Methods A total of 69 E. coli and 27 K. pneumoniae isolates were obtained from three Gaza hospitals and recovered from urine, wound swabs, blood and ear discharge. The screening for metallo-β-lactamases (MBLs) was performed by using the imipenem-EDTA disc synergy test. The detection of β-lactamases genes, detection of non-β-lactam genes and the characterization of integrons were performed by PCR and sequencing. The clonal relationship among the isolates was determined by pulsed-field gel electrophoresis (PFGE). Results Our study showed that 4 E. coli (5.8%) and 5 K. pneumoniae (18.5%) were positive by the imipenem-EDTA disc synergy test. BlaVIM-4 was detected in six isolates and blaVIM-28 was identified in three isolates. The β-lactamases genes in the VIM-producing K. pneumoniae isolates were blaCTX-M-15 (n=3), blaCTX-M-14 (n=1), blaSHV-1 (n=3), blaSHV-12 (n=1), blaTEM-1 (n=1) and blaOXA-1 (n=1). Aac(6')-Ib-cr gene was confirmed in four E. coli and in two K. pneumoniae isolates. QnrS1 was identified in two K. pneumoniae isolates. The class 1 integron was identified with the different gene cassette; dfrA17-aadA5, dfrA5, dfrA12-orf-aadA2 and dfrA17-aadA5 were identified. Conclusions Our study indicated for the first time the emergence of multidrug-resistant VIM-containing K. pneumoniae and E. coli isolates of clinical origin in Gaza Strip hospitals.

Purpose Metaplastic breast cancer (MBC) is a rare, aggressive variant of breast cancer that has been associated with poor clinical outcomes, as has triple-negative breast (TNBC) cancer. Limited studies compare the clinical characteristics and prognosis of MBC to TNBC. This study uses a large, contemporary US cancer database to compare clinical characteristics and survival outcomes for patients with MBC to those with TNBC. Methods The National Cancer Database was queried for women with cT1-4N1-3M0 MBC or TNBC diagnosed between 2004 and 2013 and treated with definitive surgery. Chi-squared analysis was performed to determine differences between the cohorts. Kaplan-Meier curves compared overall survival (OS), and Cox regression determined patient factors associated with OS. Results Altogether, 55,847 patients met the inclusion criteria; 50,705 (90.8%) had TNBC and 5,142 (9.2%) had MBC. Most patients had no comorbid conditions (82%), N0 disease (71%), poorly differentiated histology (77%), received chemotherapy (87%), and received radiation therapy (60%). Amongst all patients, patients with TNBC disease were observed to have greater OS than those with MBC (5-year OS 72.0% vs 55.8%, p, Highlights • Metaplastic breast cancer is associated with poor clinical outcomes. • Metaplastic breast cancer associated with worse survival than patients with triple negative invasive ductal carcinoma. • Radiation therapy and chemotherapy associated with improved survival for patients with metaplastic breast cancer.

Intruduction Radiation and immunotherapy have separately been shown to confer survival advantages to patients with extensive-stage small cell lung cancer (ESCLC), but failure rates remain high and combination therapy has been understudied. In this single-arm phase I trial (NCT02402920), we assessed the safety of combining pembrolizumab with thoracic radiotherapy (TRT) after induction chemotherapy for SCLC. Methods Patients with ESCLC who had completed chemotherapy received TRT with pembrolizumab. The maximum tolerated dose of pembrolizumab was assessed by 3+3 dose-escalation; doses began at 100 mg and increased in 50 mg increments to 200 mg. Pembrolizumab was given every 3 weeks for up to 16 cycles; TRT was prescribed as 45 Gy in 15 daily fractions. Toxicity was evaluated with the Common Terminology Criteria for Adverse Events v4.0. The primary endpoint was safety of the combined therapy based on the incidence of dose-limiting toxicity in the 35 days following initiation of treatment. Results Thirty-eight patients with ESCLC (median age 65 years, range: 37–79 years) were enrolled from September 2015 through September 2017; 33 received per-protocol treatment, and all tolerated pembrolizumab at 100 to 200 mg with no dose-limiting toxicity in the 35-day window. There were no grade 4-5 toxicities; 2 (6%) patients experienced grade 3 events (n = 1 rash, n = 1 asthenia/paresthesia/autoimmune disorder) that were unlikely/doubtfully related to protocol therapy. The median follow-up time was 7.3 months (range: 1–13 months); median progression-free and overall survival times were 6.1 months (95% confidence interval: 4.1–8.1) and 8.4 months (95% confidence interval: 6.7-10.1). Conclusions Concurrent pembrolizumab-TRT was tolerated well with few high-grade adverse events in the short-term; progression-free and overall survival rates are difficult to interpret due to heterogeneity in eligibility criteria (e.g., enrolling progressors on induction chemotherapy). Although randomized studies have shown benefits to TRT alone and immunotherapy alone, the safety of the combined regimen supports further investigation as a foundational approach for future prospective studies.

Although isolated local (LRs) and regional recurrences (RRs) constitute a minority of post-stereotactic ablative radiotherapy (SABR) relapses, their management is becoming increasingly important as the use of SABR continues to expand. However, few evidence-based strategies are available to guide treatment of these potentially curable recurrences. On behalf of the Advanced Radiation Technology Committee (ART) of the International Association for the Study of Lung Cancer (IASLC), this article was written to address management of recurrent disease. Topics discussed include diagnosis and workup, including the roles of volumetric and functional imaging as well as histopathologic methods; clinical outcomes after salvage therapy; patterns of recurrence after salvage therapy; and management options. Our main conclusions are that survival for patients with adequately salvaged LRs is similar to that for patients after primary SABR without recurrence, and survival for those with salvaged RRs (regardless of nodal burden or location) is similar to that of patients with de novo stage III disease. Although more than half of patients who undergo salvage do not develop a second relapse, the predominant pattern of second failure is distant, especially for RRs. Management requires rigorous multidisciplinary coordination. Isolated LRs can be managed with resection and nodal dissection, repeat SABR, thermal ablation, or systemic therapies. RRs can be treated with combined chemoradiotherapy, radiation or chemotherapy alone, or supportive services. Finally, regular and structured follow-up is recommended after post-SABR salvage therapy.

For the first time in the literature, experimental determination of entire sets of exact interdiffusion coefficients in quaternary and quinary alloy systems is reported. Using the method of body-diagonal diffusion couple, a set of nine quaternary interdiffusion coefficients were evaluated in Fe–Ni–Co–Cr and a set of sixteen quinary interdiffusion coefficients were determined in a Fe–Ni–Co–Cr–Mn system, both at approximately equimolar compositions. Regions of uphill interdiffusion and zero flux planes were observed for nickel and cobalt in quinary couples, indicating the existence of strong diffusional interactions in Fe–Ni–Co–Cr–Mn alloys. The strong diffusional interactions were also manifested in the large magnitudes of cross coefficients in both the systems. The existence of strong diffusional interactions in high-entropy alloys (HEAs) as observed through experimentally determined interdiffusion coefficients in this study establishes beyond doubt the fact that cross interdiffusion coefficients cannot be ignored in HEAs.

Aqueous rechargeable aluminium-ion batteries (AIBs) are promising post lithium-ion battery candidates. However, the capacity and cycling stability are limited by the cathode materials, hindering their widespread application. Herein, bronze-type vanadium dioxide (VO2–B) holey nanobelts have been designed as the cathode material to improve both the capacity and cycling stability for high-performance aqueous AIBs. Benefiting from the unique shear structure and two-dimensional holey nanobelt morphology, the VO2–B electrode delivers a superior specific capacity of up to 234 mA h g−1 at 150 mA g−1 and exhibits a high capacity retention of 77.2% over 1000 cycles at 1 A g−1, which are among the best cathode performances reported for aqueous AIBs. Moreover, a combination of electro-kinetic analysis and ex situ structural evolution characterization experiments reveals the reaction storage mechanism underlying the superior performance. Specifically, proton and Al3+ ions can reversibly co-intercalate/de-intercalate into/from VO2–B. The integration of shear structure and unique holey nanobelts may open the route to the design of high-performance cathodes for multi-valence ion batteries. National Research Foundation (NRF) Accepted version This work was financially supported by the National Research Foundation of Singapore (NRF) Investigatorship Award Number NRFI2017-08/NRF2016NRF-NRFI001-22.

In this study, we report on the development of triboelectric energy generators (TEGs) made of porous polyvinylidene fluoride (PVDF) and bacterial cellulose (BC) layers and their demonstration as a self-powered sensor for remote security applications. PVDF films are fabricated by room temperature solution casting at different relative humidity (RH) with denser, stronger, and transparent PVDF films obtained at lower relative humidity. Among all the PVDF film based TEGs, the triboelectric generator (TEG) made of the film prepared at a low relative humidity of 10% (PVDF10) shows the highest voltage, current and power density of 410 V, 14.8 μA (current density: 0.57 μA cm−2) and 3.5 mW, respectively and a maximum power density of 0.136 mW cm−2 at 33 MΩ. Enhancement in the value of power density is almost three-fold as compared to that of the PVDF film cast at a high relative humidity of 54% (PVDF54). The high output response of the PVDF10 based TEG is attributed to the rough surface, higher γ-phase fraction, and high dielectric constant of the PVDF10 film. Finally, the potential of a TEG device for practical application in biomechanical energy harvesting is demonstrated by lighting up more than 100 light-emitting diodes using a low-frequency foot strike as a mechanical stimulus along with lighting up of a 5-bit 7 segment LCD display. The device was also used as a self-powered motion sensor for application in wireless security, which could be practically realistic. Overall, the study demonstrates the possible applications of PVDF thin film based TEG devices, which can be fabricated using an easy, room temperature, and environment-friendly processing method.

Purpose The adenoid cystic carcinoma (ACC), Erbitux, and Particle Therapy (ACCEPT) phase 1/2 trial (NCT01192087) evaluated a combined-modality approach (concurrent cetuximab and intensity modulated radiation therapy with carbon ion boost) for newly diagnosed nonmetastatic head and neck ACC. Methods and Materials Twenty-three patients with ACC were enrolled between June 2012 and June 2017 after initial diagnosis or postoperatively. All received a 400 mg/m2 cetuximab loading dose a week before radiation therapy, followed by weekly 250 mg/m2 doses starting on the first day of radiation therapy. The carbon ion radiation therapy boost was 24 Gy (relative biological effectiveness) in 8 daily fractions, followed by intensity modulated radiation therapy (54 Gy). The primary endpoint was safety and feasibility (defined based on Common Terminology Criteria for Adverse Events grade ≥3 events). Secondary endpoints included local and distant relapse, disease-free survival, and overall survival. Results Disease was most commonly in the paranasal sinuses (30%), palate (17%), and nasopharynx (17%). Nine (39%) patients underwent surgery (R1: 22%, R2: 78%). Median follow-up was 38.5 months. No patients experienced grade 4 to 5 events. Rates of grade 3 rash and radiation dermatitis were 17% and 22%, respectively. Grade 2 and 3 mucositis and dysgeusia occurred in 43% and 48% and in 9% and 0%, respectively. Grade 2 to 3 dysphagia and xerostomia were present in 43% and 4% and in 26% and 0%, respectively. At last follow-up, 5 (22%) patients experienced in-field relapse and 6 (26%) developed distant metastases. The 3-year disease-free survival was 67%, and median overall survival was 54 months. Conclusions Outcomes of this trial were satisfactory. Although the trial did not meet the predefined criteria of feasibility owing to the comparatively high rates of grade 3 dermatitis, numbers are comparable to existing data on cetuximab + radiation therapy.

Nodal involvement in malignant pleural mesothelioma (MPM) is a poor prognostic factor, and management remains highly debated. Because there are no prospective trials for this population, this investigation addressed a major knowledge gap by examining national practice patterns as well as survival outcomes. The National Cancer Database was queried for newly diagnosed cN1-3M0 MPM. Multivariable logistic regression ascertained factors associated with administering surgery. Kaplan-Meier analysis assessed overall survival (OS); multivariable Cox proportional hazards modeling examined factors associated with OS. No statistical intergroup comparisons were made herein. This was primarily owing to undeniable selection biases in these heterogeneous datasets; the presence of incomplete and inadequately granular clinical information (eg, intent and selection of treatment, preoperative assessment) cannot be accounted for by propensity matching or other such algorithms, thus potentially leading to misinterpretation. Of 2548 patients, 20%, 70%, and 9% had N1, N2, and N3 disease, respectively. Overall, 13% received surgery/chemotherapy, 47% underwent chemotherapy alone, 30% were observed, and 5% received resection without chemotherapy (5% had unknown treatment information). The median OS for all patients was 9.2 months. Relative to N1 cases, N2+ subjects were less likely to undergo resection, and they also experienced lower OS (P0.05 for both). The median OS in N1, N2, and N3 patients was 10.0, 9.1, and 8.5 months, respectively. In summary, nodal status is a prognostic factor in cN+ MPM. Expected outcomes for the overall population and by nodal classification are described, which should be considered when patients and multidisciplinary providers jointly weigh management options. Careful patient selection in this population is necessary, encompassing factors such as histology, age, performance status, and location(s) of nodal burden.

It is crucial to economically justify the use of promising therapies such as stereotactic ablative radiotherapy (SABR) for oligometastatic disease (OMD). The goal of this systematic review was to provide a summative evaluation of publications that analyzed the cost-effectiveness (CE) of SABR for OMD. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided methodology, PubMed and Embase were searched for modeling-based CE studies for various forms of limited metastatic disease. Only full publications that specifically compared SABR with a systemic therapy-based approach were included. In total, 9 studies met inclusion criteria; 4 pertained to OMD with mixed histologies, 2 to oligometastatic non-small cell lung cancer, 1 to pulmonary OMD, 1 to liver OMD, and 1 to low-volume oligorecurrent castration-sensitive prostate cancer. All but 1 investigation illustrated that SABR was cost-effective for the studied population (or a subpopulation); of these studies, the incremental CE ratios for SABR (when reported) ranged from $28,000/quality-adjusted life-year (QALY) to $55,000/QALY. Of studies that reported the probability of SABR being cost-effective at common willingness-to-pay values, the median (range) probability of achieving CE was roughly 61% (30%-88%) at a $50,000/QALY threshold and 78% (31%-100%) at a $100,000/QALY threshold. Taken together, the available evidence suggests that SABR appears to be a cost-effective approach for OMD, which has implications for value-based oncologic practice and construction of future health policies. However, reassessment is required in the context of modern systemic therapies (eg, immunotherapy) as well as long-term follow-up of existing and newly reported randomized trials. Prudent patient selection remains the single most important factor influencing the CE of SABR for OMD.

Purpose Recent randomized studies have suggested improvements in progression-free and overall survival with the addition of stereotactic body radiation therapy (SBRT, also known as SABR) in patients with oligometastatic non-small cell lung cancer. Given the novelty and complexity of incorporating SBRT in the oligometastatic setting, the multidisciplinary American Radium Society Lung Cancer Panel was assigned to create appropriate use criteria on SBRT as part of consolidative local therapy for patients with oligometastatic and oligoprogressive non-small cell lung cancer. Methods and Materials A review of the current literature was conducted from January 1, 2008, to December 25, 2020, using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to systematically search the PubMed database to retrieve a comprehensive set of relevant articles. Results Based on representation in existing randomized trials, the panel defined the term “oligometastasis” as ≤3 metastatic deposits (not including the primary tumor) in the previously untreated setting or after first-line systemic therapy after the initial diagnosis. “Oligoprogression” also referred to ≤3 discrete areas of progression in the setting of prior or ongoing receipt of systemic therapy. In all appropriate patients, the panel strongly recommends enrollment in a clinical trial whenever available. For oligometastatic disease, administering first-line systemic therapy followed by consolidative radiation therapy (to all sites plus the primary/nodal disease) is preferred over up-front radiation therapy. Owing to a dearth of data, the panel recommended that consolidative radiation therapy be considered on a case-by-case basis for 4 to 5 sites of oligometastatic disease, driver mutation-positive oligometastatic disease without progression on up-front targeted therapy, and oligoprogressive cases. Conclusions Although SBRT/SABR appears to be both safe and effective in treating patients with limited metastatic sites of disease, many clinical circumstances require individualized management and strong multidisciplinary discussion on account of the limited existing data.

Background Adding radiotherapy (RT) to systemic therapy improves progression-free survival (PFS) and overall survival (OS) in oligometastatic non-small cell lung cancer (NSCLC). Whether these findings translate to epidermal growth factor receptor (EGFR)–mutated NSCLC remains unknown. The SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated synchronous oligometastatic NSCLC and randomized to upfront RT vs no RT; we now report the prespecified interim analysis at 68% accrual. Methods Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per amplification refractory mutation system or next generation sequencing), with synchronous (newly diagnosed, treatment naïve) oligometastatic (≤5 metastases; ≤2 lesions in any one organ) NSCLC without brain metastases. All patients received a first-generation TKI (gefitinib, erlotinib, or icotinib), and randomization was between no RT vs RT (25-40 Gy in 5 fractions depending on tumor size and location) to all metastases and the primary tumor/involved regional lymphatics. The primary endpoint (intention to treat) was PFS. Secondary endpoints included OS and toxicities. All statistical tests were 2-sided. Results A total of 133 patients (n = 65 TKI only, n = 68 TKI with RT) were enrolled (2016-2019). The median follow-up was 23.6 months. The respective median PFS was 12.5 months vs 20.2 months (P Conclusions As compared with a first-line TKI alone, addition of upfront local therapy using RT statistically significantly improved PFS and OS for EGFR-mutated NSCLC.

Poor bioavailability and aqueous solubility represent a major constraint during the development of new API molecules and can influence the impact of new medicines or halt their approval to the market. Cocrystals offer a novel and competitive advantage over other conventional methods with respect towards the substantial improvement in solubility profiles relative to the single-API crystals. Furthermore, the production of such cocrystals through atomization-based methods allow for greater control, with respect to particle size reduction, to further increase the solubility of the API. Such atomization-based methods include supercritical fluid methods, conventional spray drying and electrohydrodynamic atomization/electrospraying. The influence of process parameters such as solution flow rates, pressure and solution concentration, in controlling the solid-state and final particle size are discussed in this review with respect to atomization-based methods. For the last decade, literature has been attempting to catch-up with new regulatory rulings regarding the classification of cocrystals, due in part to data sparsity. In recent years, there has been an increase in cocrystal publications, specifically employing atomization-based methods. This review considers the benefits to employing atomization-based methods for the generation of pharmaceutical cocrystals, examines the most recent regulatory changes regarding cocrystals and provides an outlook towards the future of this field.

Background Radiotherapy can induce cardiac injury in left-sided breast cancer cases. Cardiac-sparing irradiation using the deep inspiration breath-hold (DIBH) technique can achieve substantial dose reduction to vulnerable cardiac substructures compared with free breathing (FB). This study evaluated the dosimetric differences between both techniques at a single institution. Methods From 2017 to 2019, 130 patients with left-sided breast cancer underwent breast-conserving surgery (BCS; n = 121, 93.1%) or mastectomy (ME; n = 9, 6.9%) along with axillary lymph node staging (n = 105, 80.8%), followed by adjuvant irradiation in DIBH technique; adjuvant systemic therapy was included if applicable. 106 (81.5%) patients received conventional and 24 (18.5%) hypofractionated irradiation. Additionally, 12 patients received regional nodal irradiation. Computed tomography (CT) scans in FB and DIBH position were performed for all patients. Intrafractional 3D position monitoring of the patient surface in deep inspiration and breath gating was performed using Sentinel and Catalyst HD 3D surface scanning systems (C-RAD, Catalyst, C‑RAD AB, Uppsala, Sweden). Individual coaching and determination of breathing amplitude during the radiation planning CT was performed. Three-dimensional treatment planning was performed using standard tangential treatment portals (6 or 18 MV). The delineation of cardiac structures and both lungs was done in both the FB and the DIBH scan. Results All dosimetric parameters for cardiac structures were significantly reduced (p p p p p p Conclusion For all ascertained dosimetric parameters, a significant dose reduction could be achieved in DIBH technique.

In the present work, we have tested the potency of iodine-loaded agar transdermal patches (5 mg/cm2) for the treatment of infected diabetic wounds in the Wistar rat model. The rats were treated wit...

The hippocampus, an extension of the temporal part of the cerebral cortex, plays a crucial role in learning and memory. Structural and functional complexity within the hippocampus is greatly affected by a variety of external environmental stimuli including alteration in the light-dark (LD) cycle. The effect of altered LD cycle in learning and memory associated cognitive impairment has been reported in rodents. However, a comparative study of underlying neuronal changes between nocturnal and diurnal species is not well explored. The objective of the present study was to explore the morphological changes in hippocampal CA1 and DG neurons in response to prolonged constant condition