Autologous haematopoietic stem cell transplantation as a first-line disease-modifying therapy in patients with 'aggressive' multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. OBJECTIVES: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS. METHODS: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated. RESULTS: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans. CONCLUSION: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.

Guidelines for the management of diabetes services and patients during the COVID-19 pandemic.

The UK National Diabetes Inpatient COVID Response Group was formed at the end of March 2020 to support the provision of diabetes inpatient care during the COVID pandemic. It was formed in response to two emerging needs. First to ensure that basic diabetes services are secured and maintained at a time when there was a call for re-deployment to support the need for general medical expertise across secondary care services. The second was to provide simple safe diabetes guidelines for use by specialists and non-specialists treating inpatients with or suspected of COVID-19 infection. To date the group, comprising UK-based specialists in diabetes, pharmacy and psychology, have produced two sets of guidelines which will be continually revised as new evidence emerges. It is supported by Diabetes UK, the Association of British Clinical Diabetologists and NHS England.

Mitogen-activated protein kinases (MAPKs) are modulated during in vitro and in vivo infection with the intracellular bacterium Burkholderia pseudomallei.

Burkholderia pseudomallei is a Gram-negative intracellular bacterium that causes the disease melioidosis. The disease can be fatal if left untreated or when antibiotic therapy is delayed and total clearance of the pathogen from the host is often not accomplished with current therapies. Thus, new therapeutic approaches for the treatment of infections caused by B. pseudomallei are required. To better understand host responses to B. pseudomallei infection, the activation of key proteins involved in the TLR inflammatory cascade was measured by western blotting. Activation of the mitogen-activated protein kinases (MAPKs) p38 and ERK were both significantly altered during both in vitro and in vivo infection. In considering an approach for therapy of B. pseudomallei infection the inhibition of ERK was achieved in vitro using the inhibitor PD0325901, along with decreased TNF-α production. However, the reduction in phosphorylated ERK and TNF-α release did not correspond with decreased bacterial replication or enhance clearance from infected macrophages. Despite this apparent lack of effect on the intracellular growth of B. pseudomallei in vitro, it is not clear what effect inhibition of ERK activation might have on outcome of disease in vivo. It may be that decreasing the levels of TNF-α in vivo could aid in reducing the overactive immune response that is known to ensue following B. pseudomallei infection, thereby increasing host survival.

Mitogen-activated protein kinases (MAPKs) are modulated during Francisella tularensis infection, but inhibition of extracellular-signal-regulated kinases (ERKs) is of limited therapeutic benefit.

Francisella tularensis is a Gram-negative intracellular bacterium that causes the disease tularemia. The disease can be fatal if left untreated and there is currently no licenced vaccine available; the identification of new therapeutic targets is therefore required. Toll-like receptors represent an interesting target for therapeutic modulation due to their essential role in generating immune responses. In this study, we analysed the in vitro expression of the key mitogen-activated protein kinases (MAPKs) p38, JNK and ERK in murine alveolar macrophages during infection with F. tularensis. The phosphorylation profile of ERK highlighted its potential as a target for therapeutic modulation and subsequently the effect of ERK manipulation was measured in a lethal intranasal F. tularensis in vivo model of infection. The selective ERK1/2 inhibitor PD0325901 was administered orally to mice either pre- or post-challenge with F. tularensis strain LVS. Both treatment regimens selectively reduced ERK expression, but only the pre-exposure treatment produced decreased bacterial burden in the spleen and liver, which correlated with a significant reduction in the pro-inflammatory cytokines IFN-γ, MCP-1, IL-6, and TNF-α. However, no overall improvements in survival were observed for treated animals in this study. ERK may represent a useful therapeutic target where selective dampening of the immune response (to control the damaging pathology seen during infection) is combined with antibiotic treatment required to eradicate bacterial infection. This combination treatment strategy has been shown to be effective in other models of tularemia.

Decidualization of Endometriosis in Macaques.

The decidua is the superficial portion of endometrium that transforms, or decidualizes, under the influence of progesterone to nourish the early embryo during pregnancy. Deciduae outside the uterus are found in nearly 100% of human pregnancies. This condition, known as deciduosis, may mimic malignancy, resulting in additional diagnostic procedures that place the mother, baby, or both at risk. Deciduosis has been described in both Old World and New World nonhuman primates in conjunction with pregnancy and after treatment with exogenous progestins. Here the authors present 6 cases of deciduosis associated with endometriotic lesions in female rhesus and cynomolgus macaques (Macaca mulatta and Macaca fascicularis). Full diagnostic necropsies with histologic analyses were performed on all animals. Deciduae were stained with hematoxylin and eosin and by immunohistochemistry for vimentin, CD10, progesterone receptor, estrogen receptor, desmin, cytokeratin, kermix P8, chorionic gonadotropin, human placental lactogen, and calretinin. The most common clinical signs were abdominal pain (4 of 6) and anorexia (2 of 6). At necropsy, macaque uteri were often enlarged or disfigured (4 of 6) with abundant fibrous adhesions (5 of 6). Affected tissue consisted of epithelial-lined cysts and decidualized stroma with scattered gamma/delta T cells. Decidualized stromal cells were large and polyhedral with abundant cytoplasm and round vesicular nuclei. They stained positive for vimentin, CD10, progesterone, and estrogen. In summary, these cases illustrate deciduosis in 6 nonhuman primates with endometriosis. Understanding decidualization in nonhuman primates will aid in elucidating the pathophysiology of deciduosis during pregnancy or endometriosis and potentially lead to new interventions.

The Ipswich Touch Test: a simple and novel method to screen patients with diabetes at home for increased risk of foot ulceration.

AIMS: The Ipswich Touch Test is a novel method to detect subjects with diabetes with loss of foot sensation and is simple, safe, quick, and easy to perform and teach. This study determines whether it can be used by relatives and/or carers to detect reduced foot sensation in the setting of the patient's home. METHODS: The test involves lightly and briefly (1-2 s) touching the tips of the first, third and fifth toes of both feet with the index finger. Reduced foot sensation was defined as ≥ 2 insensate areas. Patients due to attend clinic over a 4-week period were invited by post. The invitation contained detailed instructions and a sheet for recording the results. The findings were compared with those obtained in clinic using the 10-g monofilament at the same six sites. RESULTS: Of 331 patients (174 males), 25.1% (n = 83) had ≥ 2 insensate areas to 10-g monofilament testing. Compared with this, the Ipswich Touch Test at home had a sensitivity of 78.3% and a specificity of 93.9%. The predictive values of detecting 'at-risk' feet were positive at 81.2% and negative at 92.8%. The likelihood ratios were positive at 12.9 and negative at 0.23. CONCLUSIONS: With clearly written instructions, this simple test can be used by non-professionals to accurately assess for loss of protective sensation. We believe that the Ipswich Touch Test may also be a useful educational adjunct to improve awareness of diabetes foot disease in patients and relatives alike and empower them to seek appropriate care if sensation was found to be abnormal.

Putting the 'C' back into continuous renal replacement therapy.

It may seem obvious that continuous renal replacement therapy (CRRT) means that the treatment is truly continuous--administered without interruption on a 24/7 basis. In reality, a number of barriers limit the continuous aspect of CRRT. This article describes how nursing staff of an inpatient dialysis unit in a large Midwestern academic institution identified these barriers and developed and implemented a multifaceted plan to optimize CRRT.

A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper.

BACKGROUND: Haematopoietic stem cell transplantation (HSCT) has been tried in the last 15 years as a therapeutic option in patients with poor-prognosis autoimmune disease who do not respond to conventional treatments. Worldwide, more than 600 patients with multiple sclerosis (MS) have been treated with HSCT, most of them having been recruited in small, single-centre, phase 1-2 uncontrolled trials. Clinical and magnetic resonance imaging outcomes from case series reports or Registry-based analyses suggest that a major response is achieved in most patients; quality and duration of response are better in patients transplanted during the relapsing-remitting phase than in those in the secondary progressive stage. OBJECTIVES: An interdisciplinary group of neurologists and haematologists has been formed, following two international meetings supported by the European and American Blood and Marrow Transplantation Societies, for the purpose of discussing a controlled clinical trial, to be designed within the new scenarios of evolving MS treatments. CONCLUSIONS: Objectives of the trial, patient selection, transplant technology and outcome assessment were extensively discussed. The outcome of this process is summarized in the present paper, with the goal of establishing the background and advancing the development of a prospective, randomized, controlled multicentre trial to assess the clinical efficacy of HSCT for the treatment of highly active MS.

Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus.

Interferons are circulating factors that bind to cell surface receptors, activating a signaling cascade, ultimately leading to both an antiviral response and an induction of growth inhibitory and/or apoptotic signals in normal and tumor cells. Attempts to exploit the ability of interferons to limit the growth of tumors in patients has met with limited results because of cancer-specific mutations of gene products in the interferon pathway. Although interferon-non-responsive cancer cells may have acquired a growth/survival advantage over their normal counterparts, they may have simultaneously compromised their antiviral response. To test this, we used vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus exquisitely sensitive to treatment with interferon. VSV rapidly replicated in and selectively killed a variety of human tumor cell lines even in the presence of doses of interferon that completely protected normal human primary cell cultures. A single intratumoral injection of VSV was effective in reducing the tumor burden of nude mice bearing subcutaneous human melanoma xenografts. Our results support the use of VSV as a replication-competent oncolytic virus and demonstrate a new strategy for the treatment of interferon non-responsive tumors.

Cyclophosphamide-bortezomib-dexamethasone compared with bortezomib-dexamethasone in transplantation-eligible patients with newly diagnosed multiple myeloma.

Introduction: Cyclophosphamide-bortezomib-dexamethasone (CyBorD) is considered a standard induction regimen for transplant-eligible patients with newly diagnosed multiple myeloma (mm). It has not been prospectively compared with bortezomib-dexamethasone (Bor-Dex). We aimed to compare the efficacy of CyBorD and Bor-Dex induction in transplant-eligible patients. Methods: In a retrospective observational study at a single tertiary centre, all patients with transplant-eligible mm who received induction with CyBorD or Bor-Dex between March 2008 and April 2016 were enrolled. Progression-free survival (pfs), response, and stem-cell collection for a first autologous stem-cell transplantation (ahsct) were compared. Results: Of 155 patients enrolled, 78 (50.3%) had received CyBorD, and 77 (49.7%), Bor-Dex. The patients in the Bor-Dex cohort were younger than those in the CyBorD cohort (median: 57 years vs. 62 years; p = 0.0002) and more likely to have had treatment held, reduced, or discontinued (26% vs. 14.5%, p = 0.11). The stem-cell mobilization regimen for both cohorts was predominantly cyclophosphamide and granulocyte colony-stimulating factor (gcsf). Plerixafor was used more often for the CyBorD cohort (p = 0.009), and more collection failures occurred in the CyBorD cohort (p = 0.08). In patients receiving Bor-Dex, more cells were collected (9.9×106 cells/kg vs. 7.7×106cells/kg, p = 0.007). At day +100, a very good partial response or better was achieved in 75% of the CyBorD cohort and in 73% of the Bor-Dex cohort (p = 0.77). Median pfs was 3.2 years in the Bor-Dex cohort and 3.7 years in the CyBorD cohort (p = 0.56). Conclusions: Overall efficacy was similar in our patients receiving CyBorD and Bor-Dex. After ahsct, no difference in depth of response or pfs was observed. Cyclophosphamide-gcsf seems to increase collection failures and hospitalizations in patients receiving CyBorD. Prospective studies are required to examine that relationship.

Erythropoietic and reticuloendothelial function in bone marrow in dogs.

Erythropoietic and reticuloendothelial functions in bone marrow were found to be identically distributed between various bones and within individual bones in the dog.

Differential cell surface properties of vegetative Bacillus.

AIMS: The genus Bacillus encompasses a wide range of species which display varying pathogenic abilities. The hydrophobicity of a range of Bacillus species was determined to evaluate the correlation between bacterial hydrophobicity and pathogenicity. METHODS AND RESULTS: Bacterial adhesion to hydrocarbon assays were used to determine the hydrophobicity of various Bacillus species. Significant differences in the hydrophobicity of vegetative Bacilli were found. Specifically, vegetative Bacillus anthracis or Bacillus thuringiensis cells were highly hydrophobic whereas Bacillus cereus or Bacillus subtilis were only slightly hydrophobic using this test. Cell adhesion assays using A549 or J774 cells were used to demonstrate a correlation between the bacterial hydrophobicity profiles with the ability to adhere to the mammalian cell lines. CONCLUSIONS: The ability of Bacillus species to adhere to mammalian cell lines correlates with the hydrophobicity of the bacteria and also correlates with the relative pathogenicity of some of the Bacillus species tested. SIGNIFICANCE AND IMPACT OF THE STUDY: This work suggests that study of the physical-chemical properties of vegetative cells could inform future approaches for the rapid identification and discrimination of potentially pathogenic Bacilli.

Evaluating dose-limiting toxicities of MDM2 inhibitors in patients with solid organ and hematologic malignancies: A systematic review of the literature.

INTRODUCTION: Mouse double minute 2 protein (MDM2), a negative regulator of the p53 tumour suppressor gene, is frequently amplified in malignancies. MDM2 antagonists have shown efficacy in treating malignancies with MDM2 overexpression and can overcome chemoresistance in acute myeloid leukemia. We systematically evaluated the safety profile of MDM2 inhibitors in the treatment of solid organ and hematologic malignancies. MATERIALS AND METHODS: We searched Medline and EMBASE from January 1947 to November 2018 for prospective clinical studies, in English or French, investigating any MDM2 inhibitor in pediatric or adult cancers, and reporting dose and toxicity outcomes. Primary outcome was dose-limiting toxicity (DLT) and secondary outcome was death. RESULTS: The search yielded 493 non-duplicate citations. Eighteen studies of 10 inhibitors met inclusion criteria (total N = 1005 patients). Two-thirds of included studies did not define DLTs and the reporting of toxicities was highly variable. The most commonly reported DLTs were cytopenias, gastrointestinal toxicity, metabolic disturbances, fatigue and cardiovascular toxicity; there was one death attributed to treatment toxicity. CONCLUSION: MDM2 antagonists have been studied in a variety of malignancies with toxicities similar to other commonly used chemotherapy agents and may represent a safe adjuvant treatment for further study in in acute leukemia.

Rapid Decrease in KRT14 and TP53 mRNA Expression in the Buccal Mucosa of Patients Receiving Total-Body Irradiation for Allogeneic Stem Cell Transplantation.

The only curative treatment option for relapsed patients with acute myeloid leukemia (AML) is allogeneic stem cell transplantation. Depletion of hematopoietic stem cells and leukemic blast cells is achieved through the systemic administration of DNA damaging agents, including total-body irradiation (TBI) prior to transplantation. Since other tissues are radiosensitive, the identification of biomarkers could facilitate the management of additional toxicities. Buccal keratinocytes are readily accessible and could provide a source of cells for RNA analysis. In this study, we obtained miRNAs and mRNAs from daily buccal swabs collected from patients undergoing allogeneic stem cell transplantation. Unexpectedly, there was no prominent p53-induced mRNA or miRNA response in these samples, despite the fact that the p53 pathway is a well-characterized radiation-inducible response. Instead, the expression of mRNAs encoding p53 and cytokeratin 14 (TP53 and KRT14, respectively) decreased precipitously within hours of the first radiation treatment. These patients went on to develop oral mucositis, however, it is unclear whether TP53 and/or KRT14 expression are predictive of this adverse event. Larger scale analysis of buccal epithelial samples from patients undergoing allogeneic stem cell transplantation appears to be warranted.

Chlorpromazine distribution in hamsters and mice bearing transplantable melanoma.

Chlorpromazine (CPZ) distribution was measured in tissues of Syrian golden hamsters bearing Greene melanoma and in BALB/c mice bearing Harding-Passey melanoma. Distribution was evaluated as a function of time (0.5 to 14 days) and as a function of single and multiple doses (up to five) of from 5 to 50 mg CPZ per kg body weight. Routes of administration (i.p., i.v., p.o.) were compared. The physiological behavior of CPZ is of interest as it is used extensively as a tranquilizing drug (Thorazine). Further, since CPZ binds to the pigment melanin, the possibility exists of using CPZ to transport diagnostic or therapeutic agents to melanoma. It was found that, at 2 days postinjection, tumor/tissue concentration ratios exceeded 10 for metabolizing organs, such as liver and 100 for "back-ground" tissues, such as blood and muscle. Absolute concentrations of CPZ in tumor exceeding 100 microgram CPZ per g tumor were obtained with both single and multiple doses. This selective high concentration in tumor would make CPZ an ideal vehicle for the transport of boron to tumor for use in neutron capture therapy via the 10B(n, alpha)7Li reaction.

Melanin content of hamster tissues, human tissues, and various melanomas.

Melanin content (percentage by weight) was determined in both pigmented and nonpigmented tissues of Syrian golden hamsters bearing Greene melanoma. Melanin content was also measured in various other melanoma models (B-16 in C57 mice, Harding-Passey in BALB/c mice, and KHDD in C3H mice) and in nine human melanomas, as well as in selected normal tissues. The purpose was to evaluate the possible efficacy of chlorpromazine, which is known to bind to melanin, as a vehicle for boron transport in neutron capture therapy. Successful therapy would depend upon selective uptake and absolute concentration of borated compounds in tumors; these parameters will in turn depend upon melanin concentration in melanomas and nonpigmented "background" tissues. Hamster whole eyes, hamster melanomas, and other well-pigmented animal melanomas were found to contain 0.3 to 0.8% melanin by weight, whereas human melanomas varied from 0.1 to 0.9% (average, 0.35%). Other tissues, with the exception of skin, were lower in content by a factor of greater than or equal to 30. Melanin pigment was extracted from tissues, and the melanin content was determined spectrophotometrically. Measurements were found to be sensitive to the presence of other proteins. Previous procedures for isolating and quantifying melanin often neglected the importance of removing proteins and other interfering nonmelanic substances.

Secondary malignancies after bone marrow transplantation in adults.

PURPOSE: The records of 557 consecutive adult recipients of allogeneic-related and -unrelated and syngeneic bone marrow transplants (BMTs) were reviewed to determine the incidence of secondary cancers. PATIENTS AND METHODS: Four hundred fifty-six patients were transplanted for acute lymphocytic leukemia (ALL; n = 79), acute myelogenous leukemia (AML; n = 182), and chronic myelogenous leukemia (CML; n = 195); 42 patients were transplanted for aplastic anemia (AA) and 59 for a variety of other hematologic and nonhematologic disorders, malignant and nonmalignant. Conditioning regimens included high-dose chemotherapy with or without total-body irradiation (TBI). Statistical analyses determined the cumulative incidence of developing a secondary cancer and elucidated the associated risk factors. Complete records (1 to 24 years of follow-up) on all patients were available. RESULTS: Nine patients developed 10 secondary cancers for a cumulative actuarial risk of 12% (95% confidence interval [CI], 4.3 to 23.0) 11 years after transplant. The age-adjusted incidence of secondary cancer was 4.2 times higher than that of primary cancer in the general population. Eight of the 10 were epithelial in origin and three were cutaneous. TBI and acute graft-versus-host disease (GVHD) with a severity > or = grade II were associated with the development of any secondary cancer. On the other hand, chronic GVHD was a risk factor only for the development of secondary skin neoplasms. CONCLUSION: Adult recipients of BMT face a significant risk of developing a secondary malignancy. Their risk is similar to that of other patients with hematologic malignancies who are treated with chemoradiotherapy only. Epithelial tumors, rather than the more commonly reported Epstein-Barr virus (EBV)-associated lymphomas, were most common. The fact that we did not routinely use T-cell-depleted marrow grafts nor anti-T-cell immunoglobulin for the treatment of acute GVHD may explain this variance.