Radiation therapy combined with intracerebral administration of carboplatin for the treatment of brain tumors

Background: In this study we determined if treatment combining radiation therapy (RT) with intracerebral (i.c.) administration of carboplatin to F98 glioma bearing rats could improve survival over that previously reported by us with a 15 Gy dose (5 Gy × 3) of 6 MV photons.Methods: First, in order to reduce tumor interstitial pressure, a biodistribution study was carried out to determine if pretreatment with dexamethasone alone or in combination with mannitol and furosemide (DMF) would increase carboplatin uptake following convection enhanced delivery (CED). Next, therapy studies were carried out in rats that had received carboplatin either by CED over 30 min (20 μg) or by Alzet pumps over 7 d (84 μg), followed by RT using a LINAC to deliver either 20 Gy (5 Gy × 4) or 15 Gy (7.5 Gy × 2) dose at 6 or 24 hrs after drug administration. Finally, a study was carried out to determine if efficacy could be improved by decreasing the time interval between drug administration and RT.Results: Tumor carboplatin values for D and DMF-treated rats were 9.4 ±4.4 and 12.4 ±3.2 μg/g, respectively, which were not significantly different (P = 0.14). The best survival data were obtained by combining pump delivery with 5 Gy × 4 of X-irradiation with a mean survival time (MST) of 107.7 d and a 43% cure rate vs. 83.6 d with CED vs. 30-35 d for RT alone and 24.6 d for untreated controls. Treatment-related mortality was observed when RT was initiated 6 h after CED of carboplatin and RT was started 7 d after tumor implantation. Dividing carboplatin into two 10 μg doses and RT into two 7.5 Gy fractions, administered 24 hrs later, yielded survival data (MST 82.1 d with a 25% cure rate) equivalent to that previously reported with 5 Gy × 3 and 20 μg of carboplatin.Conclusions: Although the best survival data were obtained by pump delivery, CED was highly effective in combination with 20 Gy, or as previously reported, 15 Gy, and the latter would be preferable since it would produce less late tissue effects.peer-reviewe

The Demise of Islet Allotransplantation in the US: A Call for an Urgent Regulatory Update The ISLETS FOR US Collaborative

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and more than minimally manipulated human cell and tissue products (HCT/Ps). Across the world, human islets are appropriately defined as minimally manipulated tissue which has led to islet transplantation becoming a standard-of-care procedure for patients with type 1 diabetes mellitus and problematic hypoglycemia. As a result of the outdated US regulations, only eleven patients underwent allo-ITx in the US between 2011-2016 and all in the setting of a clinical trial. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both, better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States

2023 Roadmap on ammonia as a carbon-free fuel

The 15 short chapters that form this 2023 ammonia-for-energy roadmap provide a comprehensive assessment of the current worldwide ammonia landscape and the future opportunities and associated challenges facing the use of ammonia, not only in the part that it can play in terms of the future displacement of fossil-fuel reserves towards massive, long-term, carbon-free energy storage and heat and power provision, but also in its broader holistic impacts that touch all three components of the future global food-water-energy nexus

SPARC: a matricellular regulator of tumorigenesis

Although many clinical studies have found a correlation of SPARC expression with malignant progression and patient survival, the mechanisms for SPARC function in tumorigenesis and metastasis remain elusive. The activity of SPARC is context- and cell-type-dependent, which is highlighted by the fact that SPARC has shown seemingly contradictory effects on tumor progression in both clinical correlative studies and in animal models. The capacity of SPARC to dictate tumorigenic phenotype has been attributed to its effects on the bioavailability and signaling of integrins and growth factors/chemokines. These molecular pathways contribute to many physiological events affecting malignant progression, including extracellular matrix remodeling, angiogenesis, immune modulation and metastasis. Given that SPARC is credited with such varied activities, this review presents a comprehensive account of the divergent effects of SPARC in human cancers and mouse models, as well as a description of the potential mechanisms by which SPARC mediates these effects. We aim to provide insight into how a matricellular protein such as SPARC might generate paradoxical, yet relevant, tumor outcomes in order to unify an apparently incongruent collection of scientific literature

The demise of islet allotransplantation in the United States: A call for an urgent regulatory update

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and “more than minimally manipulated” human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as “minimally manipulated tissue” and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States

What did Sun Yat-sen really die of? A re-assessment of his illness and the cause of his death

Abstract This year is the 150th anniversary of the birth of Sun Yat-sen (November 12, 1866) and the 91st year following his death (March 12, 1925). It generally has been believed that the cause of his death was “liver cancer.” However, as indicated in the official autopsy report, dated March 13, 1925, of the Peking Union Medical College Hospital (PUMCH) in Beijing, the cause of his death in reality was an adenocarcinoma of the gallbladder with direct extension to the liver and diaphragm as well as widespread metastases to the peritoneal cavity. This important piece of information seems to have never been reported in the English language literature, and it was only in 2013 that the true cause of his death was stated in a one-line sentence in a non-medical Chinese online source. It had been mistakenly believed that the cause of Dr. Sun’s death was liver cancer, based on the observations made following an exploratory laparotomy, which had been performed at PUMCH on January 26, 1925. The purpose of this short report is to provide more details relating to his terminal illness and to correct the historical record for a medical audience as to the cause of the death of Sun Yat-sen, a very important figure in the history of 20th century China

A realistic appraisal of boron neutron capture therapy as a cancer treatment modality

Abstract Boron neutron capture therapy (BNCT) is a binary therapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope boron-10 is irradiated with neutrons to produce high-energy alpha particles and recoiling lithium-7 nuclei. In this Commentary we will focus on a number of papers that were presented at a Symposium entitled “Current Clinical Status of Boron Neutron Capture Therapy and Paths to the Future”, which was held in September 2017 at the China National Convention Center in Beijing. Results were presented by clinicians from Japan, Finland, the United States, the China mainland and Taiwan, China who have been working in the multiple disciplines that are required for carrying out clinical BNCT. The main focus was on the treatment of patients with malignant brain tumors, recurrent tumors of the head and neck region, and cutaneous melanomas. The results obtained in treating these patients were reported in detail and, although most of the patients with brain tumors and head and neck cancer were not cured, there was evidence of some clinical efficacy. Although there are a number of problems that must be addressed, further clinical studies to evaluate the efficacy of BNCT are warranted. First, despite considerable effort by numerous investigators over the past 40 years, there still are only two boron-containing drugs in clinical use, l-boronophenylalanine (BPA) and sodium borocaptate (BSH). Therefore, until new and more effective boron delivery agents are developed, efforts should be directed to improving the dosing and delivery of BPA and BSH. Second, due to a variety of reasons, nuclear reactor-based BNCT has ended except for its use in the China mainland and Taiwan. Therefore, the future of BNCT depends upon the results of the ongoing Phase II clinical trials that are being carried out in Japan and the soon to be initiated trials that will be carried out in Finland. If the results obtained from these clinical trials are sufficiently promising, then BNCT will have a clear path to the future, especially for patients with the therapeutically challenging malignancies that in the past have been treated with reactor-based BNCT

Boron delivery agents for neutron capture therapy of cancer

Abstract Boron neutron capture therapy (BNCT) is a binary radiotherapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope, boron-10, is irradiated with neutrons to produce high energy alpha particles. This review will focus on tumor-targeting boron delivery agents that are an essential component of this binary system. Two low molecular weight boron-containing drugs currently are being used clinically, boronophenylalanine (BPA) and sodium borocaptate (BSH). Although they are far from being ideal, their therapeutic efficacy has been demonstrated in patients with high grade gliomas, recurrent tumors of the head and neck region, and a much smaller number with cutaneous and extra-cutaneous melanomas. Because of their limitations, great effort has been expended over the past 40 years to develop new boron delivery agents that have more favorable biodistribution and uptake for clinical use. These include boron-containing porphyrins, amino acids, polyamines, nucleosides, peptides, monoclonal antibodies, liposomes, nanoparticles of various types, boron cluster compounds and co-polymers. Currently, however, none of these have reached the stage where there is enough convincing data to warrant clinical biodistribution studies. Therefore, at present the best way to further improve the clinical efficacy of BNCT would be to optimize the dosing paradigms and delivery of BPA and BSH, either alone or in combination, with the hope that future research will identify new and better boron delivery agents for clinical use

Quantitative imaging of magnesium distribution at single-cell resolution in brain tumors and infiltrating tumor cells with secondary ion mass spectrometry (SIMS).

Glioblastoma multiforme (GBM) is one of the deadliest forms of human brain tumors. The infiltrative pattern of growth of these tumors includes the spread of individual and/or clusters of tumor cells at some distance from the main tumor mass in parts of the brain protected by an intact blood-brain-barrier. Pathophysiological studies of GBM could be greatly enhanced by analytical techniques capable of in situ single-cell resolution measurements of infiltrating tumor cells. Magnesium homeostasis is an area of active investigation in high grade gliomas. In the present study, we have used the F98 rat glioma as a model of human GBM and an elemental/isotopic imaging technique of secondary ion mass spectrometry, a CAMECA IMS-3f ion microscope, for studying Mg distribution with single-cell resolution in freeze-dried brain tissue cryosections. Quantitative observations were made on tumor cells in the main tumor mass, contiguous brain tissue, and infiltrating tumor cells in adjacent normal brain. The brain tissue contained a significantly lower total Mg concentration of 4.70 ± 0.93 mmol/kg wet weight (mean ± SD) in comparison to 11.64 ± 1.96 mmol/kg wet weight in tumor cells of the main tumor mass and 10.72 ± 1.76 mmol/kg wet weight in infiltrating tumor cells (p \u3c 0.05). The nucleus of individual tumor cells contained elevated levels of bound Mg. These observations have established that there was enhanced influx and increased binding of Mg in tumor cells. They provide strong support for further investigation of altered Mg homeostasis and activation of Mg-transporting channels in GBMs as possible therapeutic targets