Spot-scanning proton therapy for early breast cancer in free breathing versus deep inspiration breath-hold.

BACKGROUND AND PURPOSE: Proton therapy for breast cancer is usually given in free breathing (FB). With the use of deep inspiration breath-hold (DIBH) technique, the location of the heart is displaced inferiorly, away from the internal mammary nodes and, thus, the dose to the heart can potentially be reduced. The aim of this study was to explore the potential benefit of proton therapy in DIBH compared to FB for highly selected patients to reduce exposure of the heart and other organs at risk. We aimed at creating proton plans with delivery times feasible with treatment in DIBH. MATERIAL AND METHODS: Sixteen patients with left-sided breast cancer receiving loco-regional proton therapy were included. The FB and DIBH plans were created for each patient using spot-scanning proton therapy with 2-3 fields, robust and single field optimization. For the DIBH plans, minimum monitor unit per spot and spot spacing were increased to reduce treatment delivery time. RESULTS: All plans complied with target coverage constraints. The median mean heart dose was statistically significant reduced from 1.1 to 0.6 Gy relative biological effectiveness (RBE) by applying DIBH. No statistical significant difference was seen for mean dose and V17Gy RBE to the ipsilateral lung. The median treatment delivery time for the DIBH plans was reduced by 27% compared to the FB plans without compromising the plan quality. INTERPRETATION: The median absolute reduction in dose to the heart was limited. Proton treatment in DIBH may only be relevant for a subset of these patients with the largest reduction in heart exposure.

Main-chain Macromolecular Hydrazone Photoswitches.

Hydrazones-consisting of a dynamic imine bond and an acidic NH proton-have recently emerged as versatile photoswitches underpinned by their ability to form thermally bistable isomers, (Z) and (E), respectively. Herein, we introduce two photoresponsive homopolymers containing structurally different hydrazones as main-chain repeating units, synthesized via head-to-tail Acyclic Diene METathesis (ADMET) polymerization. Their key difference lies in the hydrazone design, specifically the location of the aliphatic arm connecting the rotor of the hydrazone photoswitch to the aliphatic polymer backbone. Critically, we demonstrate that their main photoresponsive property, i.e., their hydrodynamic volume, changes in opposite directions upon photoisomerization (λ=410 nm) in dilute solution. Further, the polymers-independent of the design of the individual hydrazone monomer-feature a photoswitchable glass transition temperature (Tg ) by close to 10 °C. The herein established design strategy allows to photochemically manipulate macromolecular properties by simple structural changes.

Molecular Photoswitching of Main-Chain α-Bisimines in Solid-State Polymers.

Photoisomerization of chromophores usually shows significantly less efficiency in solid polymers than in solution as strong intermolecular interactions lock their conformation. Herein, we establish the impact of macromolecular architecture on the isomerization efficiency of main-chain-incorporated chromophores (i.e., α-bisimine) in both solution and the solid state. We demonstrate that branched architectures deliver the highest isomerization efficiency for the main-chain chromophore in the solid state─remarkably as high as 70% compared to solution. The macromolecular design principles established herein for efficient solid-state photoisomerization can serve as a blueprint for enhancing the solid-state isomerization efficiency for other polymer systems, such as those based on azobenzenes.

Proton therapy for early breast cancer patients in the DBCG proton trial: planning, adaptation, and clinical experience from the first 43 patients.

BACKGROUND: The Danish Breast Cancer Group (DBCG) Proton Trial randomizes breast cancer patients selected on high mean heart dose (MHD) or high lung dose (V20Gy/V17Gy) in the photon plan between photon and proton therapy. This study presents the proton plans and adaptation strategy for the first 43 breast cancer patients treated with protons in Denmark. MATERIAL AND METHODS: Forty-four proton plans (one patient with bilateral cancer) were included; 2 local and 42 loco-regional including internal mammary nodes (IMN). Nineteen patients had a mastectomy and 25 a lumpectomy. The prescribed dose was either 50 Gy in 25 fractions (n = 30) or 40 Gy in 15 fractions (n = 14) wherefrom five received simultaneous integrated boost to the tumor bed. Using 2-3 en face proton fields, single-field optimization, robust optimization and a 5 cm range shifter ensured robustness towards breathing motion, setup- and range uncertainties. An anatomical evaluation was performed by evaluating the dose after adding/removing 3 mm and 5 mm tissue to/from the body-outline and used to define treatment tolerances for anatomical changes. RESULTS: The nominal and robust criteria were met for all patients except two. The median MHD was 1.5 Gy (0.5-3.4 Gy, 50 Gy) and 1.1 Gy (0.0-1.5 Gy, 40 Gy). The anatomical evaluations showed how 5 mm shrinkage approximately doubled the MHD while 5 mm swelling reduced target coverage of the IMN below constraints. Ensuring 3-5 mm robustness toward swelling was prioritized but not always achieved by robust optimization alone emphasizing the need for a distal margin. Twenty-eight patients received plan adaptation, eight patients received two, and one received five. CONCLUSION: This proton planning strategy ensured robust treatment plans within a pre-defined level of acceptable anatomical changes that fulfilled the planning criteria for most of the patients and ensured low MHD.

Appropriateness of action prompts for hypoglycaemia and hyperglycaemia in type 2 diabetes self-management apps.

BACKGROUND: Control of blood glucose levels is needed not only to alleviate symptoms of hypoglycaemia and hyperglycaemia, but also to prevent or delay diabetes-related complications. Advice for glucose control is usually provided to patients by members of the health care team. However, many diabetes apps claim to enhance self-management of blood glucose by providing decision support to patients when an out-of-range blood glucose level is recorded. In this study, we investigated the appropriateness of action prompts provided by diabetes apps for hypoglycaemia and hyperglycaemia against evidence-based guidelines. METHODS: We used methods previously reported to identify and select diabetes apps, which were downloaded and assessed against the American Diabetes Association (ADA) guidelines. Screenshots of action prompts corresponding to low or high out-of-range blood glucose values were subjected to content analysis. RESULTS: Of 371 diabetes self-management apps evaluated, only 217 and 216 apps alerted patients about hypoglycaemia and hyperglycaemia, respectively. Of these, 20.7% (45/217) and 15.3% (33/216) also provided action prompts. We found 5.1% of apps (hypoglycaemia: 11/217; hyperglycaemia: 11/216) provided prompts that were either too general to be helpful or not aligned with ADA guidelines. Overall, only 17.9% (39/217) and 14.8% (32/216) provided appropriate action prompts for hypoglycaemia and hyperglycaemia, respectively. CONCLUSION: Less than one fifth of apps provided evidence-based steps to guide patients through hypoglycaemia and hyperglycaemia. The majority of apps failed to provide just-in-time diabetes self-management education to prevent frequent or severe episodes of hypoglycaemia and hyperglycaemia. Our findings emphasize the need for better design and quality assurance of diabetes apps.

Photo- and halochromism of spiropyran-based main-chain polymers.

Advanced functional polymeric materials based on spiropyrans (SPs) feature multi-stimuli responsive characteristics, such as a change in color with exposure to light (photochromism) or acids (halochromism). The inclusion of stimuli-responsive molecules in general - and SPs in particular - as main-chain repeating units is a scarcely explored macromolecular architecture compared to side chain responsive polymers. Herein, we establish the effects of substitution patterns on SPs within a homopolymer main-chain synthesized via head-to-tail Acyclic Diene METathesis (ADMET) polymerization. We unambiguously demonstrate that varying the location of the ester group (-OCOR) on the chromophore, which is essential to incorporate the SPs in the polymer backbone, determines the photo- and halochromism of the resulting polymers. While one polymer shows effective photochromism and resistance towards acids, the opposite - weak photochromism and effective response to acid - is observed for an isomeric polymer, simply by changing the position of the ester-linker relative to the benzopyran oxygen on the chromene unit. Our strategy represents a simple approach to manipulate the stimuli-response of main-chain SP bearing polymers and highlights the critical importance of isomeric molecular constitution on main-chain stimuli-sensitive polymers as emerging materials.

Access to Main-Chain Photoswitching Polymers via Hydroxyl-yne Click Polymerization.

Main-chain stimuli-responsive polymers synthesized via polymerization techniques that do not rely on metal-based catalysis are highly desirable for economic reasons and to avoid metal-polymer interactions. Herein, we introduce a metal-free head-to-tail organobase-catalyzed hydroxyl-yne click polymerization of an AB-type monomer to realize photoswitchable polymers featuring α-bismines as main-chain repeating units. The prepared main-chain α-bisimine-based polymers show excellent photoswitching in solution. We further post-functionalize the obtained polymers with various thiol compounds via thiol-Michael reactions to significantly lower the glass transition temperature (Tg), likely to be beneficial for the photoswitching process in the solid state. Thus, the herein introduced polymerization technique not only provides metal-free access to main-chain stimuli-responsive polymers, but also allows for the flexible post-modification of the obtained polymers to generate advanced macromolecular architectures with tunable properties.

Main chain selective polymer degradation: controlled by the wavelength and assembly.

The advent of reversible deactivation radical polymerization (RDRP) revolutionized polymer chemistry and paved the way for accessing synthetic polymers with controlled sequences based on vinylic monomers. An inherent limitation of vinylic polymers stems from their all-carbon backbone, which limits both function and degradability. Herein, we report a synthetic strategy utilizing radical ring-opening polymerization (rROP) of complementary photoreactive cyclic monomers in combination with RDRP to embed photoresponsive functionality into desired blocks of polyvinyl polymers. Exploiting different absorbances of photoreactive cyclic monomers, it becomes possible to degrade blocks selectively by irradiation with either UVB or UVA light. Translating such primary structures of polymer sequences into higher order assemblies, the hydrophobicity of the photodegradable monomers allowed for the formation of micelles in water. Upon exposure to light, the nondegradable blocks detached yielding a significant reduction in the micelle hydrodynamic diameter. As a result of the self-assembled micellar environment, telechelic oligomers with photoreactive termini (e.g., coumarin or styrylpyrene) resulting from the photodegradation of polymers in water underwent intermolecular photocycloaddition to photopolymerize, which usually only occurs efficiently at longer wavelengths and a much higher concentration of photoresponsive groups. The reported main chain polymer degradation is thus controlled by the irradiation wavelength and the assembly of the polymers.

Remote Radical Trifluoromethylation: A Unified Approach to the Selective Synthesis of γ-Trifluoromethyl α,ß-Unsaturated Carbonyl Compounds.

Site-selective trifluoromethylation of silyl dienol ethers derived from α,ß-unsaturated aldehydes, ketones, and amides was achieved for the first time in the remote γ position. This photoredox catalyzed process is quite general to compounds bearing many functionalities and is applicable to the late-stage functionalization of biorelevant molecules. The use of S-perfluoroalkyl sulfoximines as ·RF radical sources enables the generalization of the reaction to other perfluoroalkyl groups (RF = CF2H, C4F9). Importantly, an unprecedented enantioselective C(sp3)-H perfluoroalkylation process is disclosed.

Medication safety improvements during care transitions in an Australian intensive care unit following implementation of an electronic medication management system.

BACKGROUND: For patients requiring admission to the Intensive Care Unit (ICU), transfers of care (TOC) during admission to and discharge from the ICU are particularly high-risk periods for medication errors. In the Australian setting, commonly general wards and the ICU do not share an integrated Electronic Medical ecord (EMR) and specifically an Electronic Medication Management System (EMMS) as part of the EMR. PURPOSE: To evaluate the effect of a hospital wide integrated EMMS on medication error rates during ICU admission and at TOC. METHOD: A 6-month historical control study was performed before and after implementation of the EMMS in the ICU of a tertiary hospital. Prescribing errors detected by pharmacists in the study period were divided into phase 1, (pre-EMMS, 6months), phase 2 (3 months post implementation after shakedown stage) and phase 3 (next 3 months of post implementation). They were categorized as prescribing error types under system or clinical intervention. Chi square statistics and interrupted time series analysis were used to determine if there was significant change in the proportion of patients who had an error at TOC during each phase. Logistics regression was used to determine the relationship between the dependent (error type) and the independent variable (study phase) for errors that occurred during TOC. RESULTS: Errors occurred during TOC in 42 %, 64 % and 19 % of patients in phase 1, 2 and 3 respectively. There was a significant decline in the proportion of patients with an error between phase 1 and 3 (p < 0.01). During a patient's ICU admission, at least one medication error occurred in 28.3 %, 62.6 % and 25.1 % in phase 1, 2 and 3 respectively. Besides procedural errors, the likelihood of an error occurring was greatest in phase 1, compared to phase 2 and 3 across system-related error categories. CONCLUSION: Medication errors during TOC reduced following implementation of the integrated ICU EMMS. EMMS safety features facilitated reduced system related prescribing errors as well as the severity of errors made.

2-Fluoro-2-deoxy-D-glucose positron emission tomography imaging is predictive of pathologic response and survival after preoperative chemoradiation in patients with esophageal carcinoma.

BACKGROUND: The current study was performed to assess the value of 2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in predicting the pathologic response and survival of patients with esophageal carcinoma treated with preoperative chemoradiation (CRT) and tumor resection. Preliminary reports suggest that FDG-PET may be predictive of the response of esophageal carcinoma patients to preoperative CRT. METHODS: Eighty-three patients with resectable esophageal carcinoma who underwent preoperative CRT and FDG-PET and tumor resection were evaluated for pathologic response to CRT, percent residual tumor, and survival. RESULTS: The majority of patients in the current study were men (74 of 83 patients; 89%). Most tumors were adenocarcinomas (73 of 83 tumors; 88%) and clinical (EUS)T3/4 (69 tumors; 83%) or N1 (46 tumors; 55%). FDG-PET after preoperative CRT identified pathologic responders but failed to rule out microscopic residual tumor in 13 of 73 cases (18%). Pathologic response was found to correlate with the post-CRT FDG-PET standardized uptake value (SUV) (P = 0.03) and a post-CRT FDG-PET SUV of or 4 was found to be the only preoperative factor to correlate with decreased survival (2-year survival rate of 33% vs. 60%; P = 0.01). On univariate Cox regression analysis, only post-CRT FDG-PET was found to be correlated with post-CRT survival (P = 0.04). CONCLUSIONS: Post-CRT FDG-PET was found to be predictive of pathologic response and survival in patients with esophageal carcinoma who undergo preoperative CRT. Esophagectomy should still be considered even if the post-CRT FDG-PET scan is normal because microscopic residual disease cannot be ruled out.