HYPofractionated Adjuvant RadioTherapy in 1 versus 2 weeks in high-risk patients with breast cancer (HYPART): a non-inferiority, open-label, phase III randomised trial.

BACKGROUND: Breast cancer is the most common cancer in women. Radiotherapy is an important part of breast cancer treatment after surgery. Breast cancer radiotherapy is usually delivered in 3-5 weeks. This is a long duration for women with breast cancer to stay away from the family and work. We wanted to reduce this duration so that the wages loss and the logistics can be minimised for these patients. Hypofractionation, i.e. high dose per fraction, is delivered in a smaller number of days. In this study, we will compare a 1-week schedule of hypofractionated adjuvant whole breast/chest wall and/or regional nodal radiotherapy against 2 weeks for locoregional disease control, toxicities, quality of life (QoL), survival and second cancers after primary surgery in patients with breast cancer. METHODS: Eligible patients with breast cancer after mastectomy or breast conserving surgery (BCS) will be treated with a radiotherapy dose of 26 Gy in 5 fractions over 1 week in the study arm and 34 Gy in 10 fractions over 2 weeks in the control arm. The primary endpoint of this noninferiority study will be locoregional tumour control. Secondary endpoints will be early and late radiation toxicities, quality of life, contralateral primary tumours, regional and distant metastases, survival and second cancers. A total of 1018 patients will be randomised (1:1) to receive 1 week or 2 weeks of radiotherapy. An event-driven analysis will be performed after at least 94 patients have documented locoregional recurrences. Acute radiation toxicity will be assessed and scaled according to the RTOG grading system. Late radiation toxicity will be assessed with the Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer late radiation morbidity scale. Cosmetic assessment will be done using Harvard/NSABP/RTOG breast cosmesis grading scale at baseline and 3 and 5 years. QoL will be assessed with EORTC QLQ-30 and EORTC QLQ-BR 23 at baseline and 3 and 5 years. DISCUSSION: Hypofractionation reduces treatment time to half while maintaining breast cosmesis and gives control rates equal to conventional fractionation. This is possible because breast tissue can tolerate high dose per fraction. In this study, we presume that 1-week radiotherapy will be non-inferior to 2 week radiotherapy, i.e. disease control will be similar with both the schedules without additional side effects, and QoL of these patients will be maintained. If we are able to achieve these outcomes, then patients will be able to complete their radiotherapy in less duration. There is not much data on regional nodal irradiation with hypofraction in breast cancer. We have used hypofraction for regional nodal irradiation in the past and not encountered any safety issue. If we are able to prove that late-term effects are comparable in the two schedules, it will make the radiation oncologist confident about hypofractionation in breast cancer. As breast cancer is a leading cancer in females and radiation therapy is an integral part of its local management, hypofractionation will help radiation centres worldwide to meet the growing need for radiation treatment in breast cancer, particularly in developing countries where resources are limited. It will also reduce the financial burden on the patient and family. Since we will treat these patients with both simple and complex radiotherapy techniques, it will also be possible for the low-income countries to follow this trial without needing a high-end or expensive radiotherapy equipment as the planning and treatment process will be very simple. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov ID NCT04472845 and CTRI with REF/2020/09/037050.

Bilateral Renal Auto-Transplantation for Retroperitoneal Sarcomas: Is It Underutilized?

Sarcomas are a rare tumor of mesenchymal origin. The liposarcoma is the most common sarcoma of the retroperitoneum. Liposarcomas are typically low grade, and present at an advanced stage and a large size. We report a case of a large retroperitoneal liposarcoma, approximately 50 kg, encasing both kidneys, which was managed via a two-stage resection and staged renal auto-transplantation into the intra-peritoneal pelvis. The patient maintained normal renal function throughout, and remains disease free two years post-resection. Renal auto-transplantation with pelvic placement may facilitate improved margin-free resection. Renal relocation may allow the use of curative-intent ablative therapies such as radiofrequency ablation and radiation in cases of retroperitoneal recurrence.

Left main stem stenosis angioplasty with intravascular ultrasound optimisation criteria guidance using a new generation everolimus drug-eluting stent.

INTRODUCTION: Intravascular ultrasound (IVUS) is recommended in the use of left main stem (LMS) percutaneous coronary intervention (PCI). Since the LMS diameter is usually larger than other coronary arteries, a new generation everolimus drug-eluting stent (DES), Synergy Megatron DES (Boston Scientific) has better axial and radial strength allowing more post implant overexpansion and consequently better suited for LMS lesions. We performed a study to evaluate the clinical outcomes of PCI using 1) an improved IVUS protocol with optimisation targets and 2) the use of Megatron stents. MATERIALS AND METHODS: This was a study involving LMS PCI coronary lesions using the Synergy Megatron DES. An IVUS protocol using predefined optimisation targets to evaluate for stent malapposition, longitudinal stent deformation, optimal stent expansion >90% of reference lumen and appropriate distal landing zone was used in all cases. The primary end-point was procedural success, defined by successful stent implantation with <30% residual stenosis. The secondary end-point was in-hospital and 30-day major adverse cardiovascular event (MACE). RESULTS: Eight patients with significant LMS stenosis were successfully treated with the Megatron stent. The primary end-point was achieved in all patients. There were no cases of stent malapposition or longitudinal stent deformation, one case did not have optimal LMS stent expansion and one case did not have an appropriate distal landing zone. IVUS optimisation criteria were met in 6 (75%) cases. There were no complications of coronary dissection, slow or no reflow, stent thrombosis or vessel perforation. None of the patients suffered in-hospital or 30-day MACE. The average LMS MLD at baseline was 2.1 ± 0.1mm and the post-PCI LMS MLD was 4.0 ± 0.5mm, with a significant acute luminal gain of 1.9 ± 0.7mm (p<0.01). A post-PCI MSA of 17 ± 3.9 mm2 was numerically superior compared to those documented in other LMS PCI trials. CONCLUSION: This study demonstrates low rates of shortterm major adverse cardiovascular events among patients with LMS PCI using the Megatron stents. It highlights the usefulness of IVUS-guided optimisation in LMS PCI. With the use of intravascular imaging, the new generation stent technology can improve the treatment of large proximal vessels and PCI of LMS lesions.

Bio-fabrication of porous magnetic Chitosan/Fe3O4 nanocomposite using Azolla pinnata for removal of chromium - Parametric effects, surface characterization and kinetics.

In this research, a novel porous nanocomposite, namely Chitosan-iron-oxide @ Azolla pinnata nanocomposite, has been synthesized by co-precipitation and hydrothermal method. The effect of process parameter on adsorption process was investigated. Batch removal of chromium (Cr) was optimized with respect to solution pH, batch stirring time, sorbent dose, initial chromium concentration and temperature. The maximum removal efficiency was found to be 98.58%. The Fourier transform infrared (FTIR) spectroscopy and scanning electron microscope (SEM) analysis of the nano composite confirmed the presence of characteristic functional groups and porous structure of synthesized nanocomposite. The adsorption data fitted well with Langmuir adsorption isotherm (R2 = 0.996) confirming mono layer sorption and the maximum uptake was found to be 294.12 mg/g. The adsorption was found to follow pseudo second order model (R2 = 0.997). Thermodynamic studies revealed that adsorption is endothermic and spontaneous. Reusability studies have confirmed that removal efficiency attained was 85% after completion of five adsorption-desorption cycles. Electrostatic attraction, ion exchange, coordination bonding and reduction are the major mechanisms responsible for removal of chromium. Surface modification of Azolla pinnata with chitosan and iron oxide improved the ability of Azolla in the adsorption of chromium from aqueous media. The combined effects of facile synthesis, improved adsorption features and easier magnetic separation promotes Chitosan-iron-oxide @ Azolla pinnata nanocomposite as a novel adsorbent.

Orthotopic Transplantation of the Full-length Porcine Intestine After Normothermic Machine Perfusion.

Successful intestinal transplantation is currently hindered by graft injury that occurs during procurement and storage, which contributes to postoperative sepsis and allograft rejection. Improved graft preservation may expand transplantable graft numbers and enhance posttransplant outcomes. Superior transplant outcomes have recently been demonstrated in clinical trials using machine perfusion to preserve the liver. We hypothesized that machine perfusion preservation of intestinal allografts could be achieved and allow for transplantation in a porcine model. Methods: Using a translational porcine model, we developed a device for intestinal perfusion. Intestinal samples were collected at the time of organ procurement, and after 6 h of machine perfusion for gross and histologic evaluation, hourly chemistry panels were performed on the perfusate and were used for protocol optimization. Following transplantation, porcine recipient physical activity, systemic blood parameters, and vital signs were monitored for 2 d before sacrifice. Results: In initial protocol development (generation 1, n = 8 grafts), multiple metabolic, electrolyte, and acid-base derangements were measured. These factors coincided with graft and mesenteric edema and luminal hemorrhage and were addressed with the addition of dialysis. In the subsequent protocol (generation 2, n = 9 grafts), differential jejunum and ileum perfusion were observed resulting in gross evidence of ileal ischemia. Modifications in vasodilating medications enhanced ileal perfusion (generation 3, n = 4 grafts). We report successful transplantation of 2 porcine intestinal allografts after machine perfusion with postoperative clinical and gross evidence of normal gut function. Conclusions: This study reports development and optimization of machine perfusion preservation of small intestine and successful transplantation of intestinal allografts in a porcine model.

Two Compartment Evaluation of Liver Grafts During Acellular Room Temperature Machine Perfusion (acRTMP) in a Rat Liver Transplant Model.

Background: Subnormothermic machine perfusion (SNMP) of liver grafts is currently less clinically developed than normothermic and hypothermic approaches, but may have logistical advantages. At intermediate temperatures, the oxygen demand of the graft is low enough to be satisfied with an acellular perfusate, obviating the need for oxygen carrying molecules. This intermediate metabolic rate, however, is sufficient to support the production of bile, which is emerging as an important indicator of graft injury and viability. In this study, we hypothesized that the biliary compartment would be more sensitive than perfusate in detecting graft injury during SNMP. Methods: To test this hypothesis in a rat model, we performed liver transplants with DCD and control liver grafts after 1 h of acellular room temperature machine perfusion (acRTMP) or static cold storage (SCS). Point of care liver function tests were measured in biliary and perfusate samples after 1 h of machine perfusion. Following transplantation, rats were sacrificed at 24 h for assessment of post-transplant graft function and histology. Results: All point-of-care liver function tests were significantly more concentrated in the biliary compartment than the perfusate compartment during acRTMP. DCD liver grafts could be distinguished from control liver grafts by significantly higher markers of hepatocyte injury (AST, ALT) in the biliary compartment, but not in the perfusate compartment. Classical markers of cholangiocyte injury, such as gammy-glut amyl transferase (GGT), amylase (AML), and alkaline phosphatase were detectable in the biliary compartment, but not in the perfusate compartment. In comparison to SCS, graft preservation by acRTMP produced a significant survival benefit in DCD liver transplantation (75 vs. 0%, p < 0.0030). Conclusion: Together, these findings demonstrate that during acRTMP, the biliary compartment may be a more sensitive indicator of graft injury than the perfusate compartment. Moreover, acRTMP provides superior graft preservation to SCS in rat DCD liver transplantation.

Coagulation, inflammation, and CD46 transgene expression in neonatal porcine islet xenotransplantation.

BACKGROUND: Thrombosis is a known consequence of intraportal islet transplantation, particularly for xenogeneic islets. To define the origins of thrombosis after islet xenotransplantation and relate it to early inflammation, we examined porcine islets transplanted into non-human primates using a dual-transplant model to directly compare islet characteristics. METHODS: α1,3-Galactosyltransferase gene-knockout (GTKO) islets with and without expression of the human complement regulatory transgene CD46 (hCD46) were studied. Biologically inert polyethylene microspheres were used to examine the generic pro-thrombotic effects of particle embolization. Immunohistochemistry was performed 1 and 24 hours after transplantation. RESULTS: Xeno-islet transplantation activated both extrinsic and intrinsic coagulation pathways. The intrinsic pathway was also initiated by microsphere embolization, while extrinsic pathway tissue factor (TF) and platelet aggregation were more specific to engrafted islets. hCD46 expression significantly reduced TF, platelet, fibrin, and factor XIIIa accumulation in and around islets but did not alter intrinsic factor activation. Layers of TF+ cells emerged around islets within 24 hours, particularly co-localized with vimentin, and identified as CD3+ and CD68+ cells inflammatory cells. CONCLUSIONS: These findings detail the origins of thrombosis following islet xenotransplantation, relate it to early immune activation, and suggest a role for transgenic hCD46 expression in its mitigation. Layers of TF-positive inflammatory cells and fibroblasts around islets at 24 hours may have important roles in the progressive events of thrombosis, inflammatory cell recruitment, rejection, and the ultimate outcome of transplanted grafts. These suggest that the strategies targeting these elements could yield more progress toward successful xenogeneic islet engraftment and survival.

Twisted intramolecular motion arrested in aggregated state emission and the nonlinear optical properties of pyrene pyrazoline derivatives.

Heterocyclic pyrene pyrazoline moieties containing similar structures but with differences in thiophene (PPT), furan (PPF) and pyridine (PPP) substitutions at the terminal molecules were synthesized. Their aggregation behaviour in THF-water mixtures was investigated and results demonstrated that PPT and PPP exhibited aggregation-induced emission (AIE), whereas PPF exhibited aggregation-induced blue-shifted emission (AIBSE). PPT and PPP provided red-shifted emission, while PPF had observed blue-shifted emission at high water fractions of 70-90%, confirming that aggregation effects played a major role in the molecular structure. Two emission peaks from locally excited and twisted intramolecular charge transfer confirmed the twisted nature from the dihedral angle values of the free reorganized molecules that were completely restricted in high water fractions due to molecular aggregation. This was further confirmed from colour Commission Internationale de l'Eclairage values as well as dynamic light scattering analysis. Third-order nonlinear optical properties were studied using a Nd:Yag laser beam Z-scan technique at 532 nm. The open aperture Z-scan revealed that PPT and PPF towards the peak point endured strong saturable absorption, whereas PPP indicated a strong reverse saturable absorption process. The AIE and AIBSE mechanisms from undergoing restricted twisting intramolecular motion in the aggregated luminogens provide great insight into new developments in AIEgen materials for these optoelectronic materials.

Selective electrochemical oxidative coupling of methane mediated by Sr2Fe1.5Mo0.5O6-δ and its chemical stability.

Efficient conversion of methane to value-added products such as olefins and aromatics has been in pursuit for the past few decades. The demand has increased further due to the recent discoveries of shale gas reserves. Oxidative and non-oxidative coupling of methane (OCM and NOCM) have been actively researched, although catalysts with commercially viable conversion rates are not yet available. Recently, [Formula: see text] (SFMO-075Fe) has been reported to activate methane in an electrochemical OCM (EC-OCM) set up with a C2 selectivity of 82.2%1. However, alkaline earth metal-based materials are known to suffer chemical instability in carbon-rich environments. Hence, here we evaluated the chemical stability of SFMO in carbon-rich conditions with varying oxygen concentrations at temperatures relevant for EC-OCM. SFMO-075Fe showed good methane activation properties especially at low overpotentials but suffered poor chemical stability as observed via thermogravimetric, powder XRD, and XPS measurements where SrCO3 was observed to be a major decomposition product along with SrMoO3 and MoC. Nevertheless, our study demonstrates that electrochemical methods could be used to selectively activate methane towards partial oxidation products such as ethylene at low overpotentials while higher applied biases result in the complete oxidation of methane to carbon dioxide and water.

Hydrogen bond interactions in the binary solutions of formamide with methanol: FTIR spectroscopic and theoretical studies.

FTIR spectroscopic studies on the binary solutions of formamide with methanol reveal the presence of "free" O - H in methanol. These "free" O - H groups are found in methanol tetramers which is confirmed from the DFT calculations. DFT calculations on the formamide dimers of five different geometries encompassing one or more of the N - H⋯O, C - H⋯O and N - H⋯N hydrogen bonds tell that N - H⋯N bonds are the strongest. Dissociation of the. N - H⋯N bonds of formamide in the binary solutions with methanol has a major impact on the NH2 symmetric stretching mode of formamide in the FTIR spectra. In these solutions the formation of 1:4 (formamide:methanol), 1:5 and 2:4 complexes are possible. These complexes are more stable than the formamide dimers, methanol tetramer and pentamer investigated in the present work. Methanol methyl group plays no role in either the self-association or heterointeraction with formamide.

An unusual case of neonatal seizures as manifestation of asymptomatic maternal hypoparathyroidism.

Neonatal hypoparathyroidism is one of the rare causes of hypocalcaemia. Several cases of neonatal hypoparathyroidism secondary to maternal hyperparathyroidism have been reported. In this case report, we have a term neonate with normal birth history who presented with late onset hypocalcemic seizures. After excluding polyendocrinopathies and related syndromes, hypocalcaemia seizures were secondary to maternal asymptomatic hypoparathyroidism. Since this is one variety of unusual case of maternal and fetal hypoparathyroidism, further testing was mandatory to confirm familial origin. This focuses on the need for every clinician to test maternal metabolic status in case of neonatal manifestations.

FTIR studies, DFT calculations and time domain reflectometry studies on tetrahydrofuran - methanol binary solutions.

FTIR signature of neat tetrahydrofuran (THF), methanol (MeOH) and their binary solutions at various molefractions (0.8:0.2 (THF:MeOH), 0.6:0.4, 0.4:0.6 and 0.2:0.8) have been recorded. Density Functional Theory (DFT) calculations have also been carried out on THF, MeOH multimers and possible THF-MeOH complex molecules. The results of FTIR studies and DFT calculations confirm the formation of 1:3 (THF:MeOH) and 1:4 complex structures with (MeOH)O - H⋯O(THF), (MeOH methyl)C - H⋯O(THF) and (THF methylene)C - H⋯O(MeOH) H-bond interactions. (MeOH)O - H⋯O(MeOH) homointeractions among the MeOH trimers and tetramers are stronger than the THF-MeOH heterointeractions in complexes. But, the stability of 1:4 complexes is more than that of the trimers and tetramers as inferred from the interaction energy values obtained by DFT calculations. Time Domain Reflectometry (TDR) study has also been carried out on the THF-MeOH binary solutions in the frequency range 10 MHz-30 GHz at 298 K. The results of dielectric studies have been correlated with that of FTIR studies and DFT calculations.

The role of human CD46 in early xenoislet engraftment in a dual transplant model.

BACKGROUND: Membrane cofactor protein CD46 attenuates the complement cascade by facilitating cleavage of C3b and C4b. In solid organ xenotransplantation, organs expressing CD46 have been shown to resist hyperacute rejection. However, the incremental value of human CD46 expression for islet xenotransplantation remains poorly defined. METHODS: This study attempted to delineate the role of CD46 in early neonatal porcine islet engraftment by comparing Gal-knocked out (GKO) and hCD46-transgenic (GKO/CD46) islets in a dual transplant model. Seven rhesus macaques underwent dual transplant and were sacrificed at 1 hour (n = 4) or 24 hours (n = 3). Both hemilivers were recovered and fixed for immunohistochemistry (CD46, insulin, neutrophil elastase, platelet, IgM, IgG, C3d, C4d, CD68, Caspase 3). Quantitative immunohistochemical analysis was performed using the Aperio Imagescope. RESULTS: Within 1 hour of intraportal infusion of xenografts, no differences were observed between the two types of islets in terms of platelet, antibody, or complement deposition. Cellular infiltration and islet apoptotic activity were also similar at 1 hour. At 24 hours, GKO/CD46 islets demonstrated significantly less platelet deposition (P = 0.01) and neutrophil infiltration (P = 0.01) compared to GKO islets. In contrast, C3d (P = 0.38) and C4d (P = 0.45) deposition was equal between the two genotypes. CONCLUSIONS: Our findings suggest that expression of hCD46 on NPIs potentially provides a measurable incremental survival advantage in vivo by reducing early thrombo-inflammatory events associated with instant blood-mediated inflammatory reaction (IBMIR) following intraportal islet infusion.

Secondary lymphoid tissue and costimulation-blockade resistant rejection: A nonhuman primate renal transplant study.

Naïve T cell activation requires antigen presentation combined with costimulation through CD28, both of which optimally occur in secondary lymphoid tissues such as lymph nodes and the spleen. Belatacept impairs CD28 costimulation by binding its ligands, CD80 and CD86, and in doing so, impairs de novo alloimmune responses. However, in most patients belatacept is ineffective in preventing allograft rejection when used as a monotherapy, and adjuvant therapy is required for control of costimulation-blockade resistant rejection (CoBRR). In rodent models, impaired access to secondary lymphoid tissues has been demonstrated to reduce alloimmune responses to vascularized allografts. Here we show that surgical maneuvers, lymphatic ligation, and splenectomy, designed to anatomically limit access to secondary lymphoid tissues, control CoBRR and facilitate belatacept monotherapy in a nonhuman primate model of kidney transplantation without adjuvant immunotherapy. We further demonstrate that animals sustained on belatacept monotherapy progressively develop an increasingly naïve T and B cell repertoire, an effect that is accelerated by splenectomy and lost at the time of belatacept withdrawal and rejection. These pilot data inform the role of secondary lymphoid tissues on the development of CoBRR and the use of costimulation molecule-focused therapies.

Effectiveness of Pelvic Floor Muscle Training Alone and in Combination With Biofeedback, Electrical Stimulation, or Both Compared to Control for Urinary Incontinence in Men Following Prostatectomy: Systematic Review and Meta-Analysis.

Background: The efficacy of pelvic floor muscle training (PFMT) alone and in combination with biofeedback (BFB), electrical stimulation (ES), or both for urinary incontinence in men following prostatectomy is inconclusive. Purpose: The purpose of this study was to determine whether PFMT works well alone or in combination with BFB, ES, or both in comparison with a control. Data Sources: The databases Ovid Medline, EMBASE, CENTRAL, Scopus, and Web of Science, and the specialized register of the Citroen Incontinence Review Group were searched from study inception to August 2017. Abstract proceedings from urological meetings, including the European Association of Urology and the American Urological Association, were also searched. Study Selection: Randomized controlled trials that compared PFMT alone and PFMT with ES, BFB, or both and no treatment, placebo, or sham were included in the review. Data Extraction, Synthesis, and Quality: Two independent reviewers completed data extraction and quality appraisal. The Grading of Recommendations, Assessment, Development, and Evaluation tool was used for quality appraisal. Meta-analysis was done with software used for preparing and maintaining Cochrane reviews. Limitations: Methodological flaws in the included studies limited internal validity. Conclusions: PFMT alone, PFMT plus BFB and ES, and PFMT plus ES were more effective than the control for urinary incontinence following prostatectomy. The effect of PFMT plus BFB on postprostatectomy incontinence remains uncertain.

Corrigendum to "The Role of Costimulation Blockade in Solid Organ and Islet Xenotransplantation".

[This corrects the article DOI: 10.1155/2017/8415205.].