Limb salvage in malignant tumours of the upper limb using vascularised fibula.

INTRODUCTION: Modern reconstructive techniques can prevent amputation in most cases of malignant musculoskeletal tumours. The free fibula has emerged as the primary method of bridging long bone gaps during limb salvage. METHODS: Limb salvage was attempted in 23 patients (15 males and eight females) aged 17-57 years. The tumour was located in the humerus in 18 patients, radius in four patients and the metacarpals in one patient. Osteogenic sarcoma was the most common tumour (11 cases) followed by Ewing's sarcoma in six patients. After neoadjuvant chemotherapy, MRI was repeated and resectability assessed. Wide local excision was performed and the bony defect bridged by free fibulae. RESULTS: All the flaps survived. The average length of defect reconstructed was 18 cm and the average time for bone union was 7 months. At a minimum follow up of 12 months, 21 patients were alive and disease free. One patient required amputation due to recurrence and one died of metastatic disease. Secondary surgery was needed in eight patients (five tendon transfers, two latissimus dorsi flap readjustments and one bone graft). Overall patient satisfaction was high with 21/23 patients having a useful limb. CONCLUSION: Limb salvage in the upper limb using vascularised fibula in patients with malignant musculoskeletal tumours can result in good tumour control along with reasonable limb function.     

Serological biomarkers of hepatocellular carcinoma in Egyptian patients

Hepatocellular carcinoma (HCC) is one of the most aggressive cancers worldwide. In Egypt, the disease is usually detected in an advanced stage at which no treatment may be effective including surgery. Early detection of the disease is thus an important goal allowing the patient to be treated before the enlargement of the tumor or its metastasis to distant organs. Tumor markers are serological agents which serum level may be useful in predicting the presence of the tumor at early stages. Alpha fetoprotein (AFP) which is the golden marker for HCC is of low sensitivity, therefore, additional markers such as alpha-L-fucosidase (AFU), transforming growth factors alpha and beta (TGF-α and TGF-β) and interleukin-8 (IL-8) are suggested to be simultaneously evaluated in order to enhance the detection of HCC. A total of 96 patients with different liver diseases such as HCC, hepatitis C virus (HCV), hepatitis B virus (HBV) and cirrhotic patients are included in this study. Sixteen healthy volunteers are used as a control group. In patients with HCC each of AFP, AFU, TGF-α and TGF-β recorded significantly higher levels than the other patient groups and controls. HCC patients recorded significantly lower level of IL-8 compared to the other patient groups but significantly higher than the control. For AFP, AFU, TGF-α, TGF-β and IL-8, at the optimal cut-off values (obtained from the receiver operating characteristic (ROC) curves), the calculated sensitivities are 46%, 72.97%, 67.56%, 54.05% and 83.8%, respectively. The simultaneous evaluation using all of the suggested markers resulted in increasing the sensitivity up to 100%. It thus recommended that, if patients with cirrhosis, as high risk patients, are subjected to regular examination using these markers in addition to AFP, HCC may be detected by 100% sensitivity in an early stage and as a consequence an effective treatment can be achieved.     

Pantothenic Acid Biosynthesis in the Parasite Toxoplasma gondii: a Target for Chemotherapy

Toxoplasma gondii is a major food pathogen and neglected parasitic infection that causes eye disease, birth defects, and fetal abortion and plays a role as an opportunistic infection in AIDS. In this study, we investigated pantothenic acid (vitamin B₅) biosynthesis in T. gondii. Genes encoding the full repertoire of enzymes for pantothenate synthesis and subsequent metabolism to coenzyme A were identified and are expressed in T. gondii. A panel of inhibitors developed to target Mycobacterium tuberculosis pantothenate synthetase were tested and found to exhibit a range of values for inhibition of T. gondii growth. Two inhibitors exhibited lower effective concentrations than the currently used toxoplasmosis drug pyrimethamine. The inhibition was specific for the pantothenate pathway, as the effect of the pantothenate synthetase inhibitors was abrogated by supplementation with pantothenate. Hence, T. gondii encodes and expresses the enzymes for pantothenate synthesis, and this pathway is essential for parasite growth. These promising findings increase our understanding of growth and metabolism in this important parasite and highlight pantothenate synthetase as a new drug target.     

The IL-1/IL-1R axis induces greater fibroblast-derived chemokine release in human papillomavirus-negative compared to positive oropharyngeal cancer

Human papillomavirus (HPV) is now recognised as a major aetiological agent in the pathogenesis of oropharyngeal carcinoma (OPC). HPV-positive tumours are associated with better outcomes compared to HPV-negative tumours, possibly due to differences in their aetiology and/or the tumour microenvironment. Increased numbers of tumour-associated leukocytes have been observed in many cancers including OPC, with variable influence on prognosis depending on the leukocyte subpopulation investigated. Whether HPV status influences leukocyte recruitment to OPC remains unknown. This in-vitro study examined differences in the chemoattractant capacity of HPV-positive and HPV-negative OPC cell lines. Gene and protein expression analysis demonstrated that whilst both monocultures of HPV-positive and HPV-negative cell lines, along with normal tonsillar fibroblasts (NTF), expressed low chemokine levels, NTF cultured with conditioned medium from HPV-negative OPC cells expressed significantly higher levels of all chemokines tested compared to NTF incubated with the medium from HPV-positive OPC cell lines. HPV-negative OPC lines expressed IL-1β mRNA whereas HPV-positive cells did not, and NTF constitutively expressed IL-1R1. Pre-treatment with the IL-R antagonist, anakinra or siRNA to IL-1R1 significantly reduced chemokine secretion from NTF stimulated with conditioned medium from HPV-negative tumour cells or recombinant IL-1β (p < 0.05). These data suggest that secretion of chemokines is driven by the interaction between HPV-negative OPC cells and stromal fibroblasts through an IL-1/IL-1R-mediated mechanism that is less prominent within the HPV-positive tumour microenvironment. These observations may explain differences in leukocyte sub-populations recruited to HPV-positive versus negative OPC and indicate that HPV status is a key determinant in controlling the inflammatory tumour microenvironment.     

Detection of lung transplant rejection in a rat model using hyperpolarized [1‐13C] pyruvate‐based metabolic imaging

The current standard for noninvasive imaging of acute rejection consists of X‐ray/CT, which derive their contrast from changes in ventilation, inflammation and edema, as well as remodeling during rejection. We propose the use of hyperpolarized [1‐¹³C] pyruvate MRI—which provides real‐time metabolic assessment of tissue—as an early biomarker for tissue rejection. In this preliminary study, we used μCT‐derived parameters and HP ¹³C MR‐derived biomarkers to predict rejection in an orthotopic left lung transplant model in both allogeneic and syngeneic rats. On day 3, the normalized lung density—a parameter that accounts for both lung volume (mL) and density (HU)—was ?0.335 (CI: ‐0.598, ?0.073) and ? 0.473 (CI: ‐0.726, ?0.220) for the allograft and isograft, respectively (not significant, 0.40). The lactate‐to‐pyruvate ratios—derived from the HP ¹³C MRI—for the allograft and isograft were 0.200 (CI: 0.161, 0.240) and 0.114 (CI: 0.074, 0.153), respectively (significant, 0.020). Both techniques showed tissue rejection on day 7. A separate sub‐study revealed CD8+ cells as the primary source of the lactate‐to‐pyruvate signal. Our study suggests that hyperpolarized (HP) [1‐¹³C] pyruvate MRI is a promising early biomarker for tissue rejection that provides metabolic assessment in real time based on changes in cellularity and metabolism of lung tissue and the infiltrating inflammatory cells, and may be able to predict tissue rejection earlier than X‐ray/CT.     

The anthocyanidin delphinidin mobilizes endogenous copper ions from human lymphocytes leading to oxidative degradation of cellular DNA

Epidemiological and experimental evidence exists to suggest that pomegranate and its juice possess chemopreventive and anticancer properties. The anthocyanidin delphinidin is a major polyphenol present in pomegranates and has been shown to be responsible for these effects. Plant polyphenols are recognized as naturally occurring antioxidants but also catalyze oxidative DNA degradation of cellular DNA either alone or in the presence of transition metal ions such as copper. In this paper we show that similar to various other classes of polyphenols, delphinidin is also capable of causing oxidative degradation of cellular DNA. Lymphocytes were exposed to various concentrations of delphinidin (10, 20, 50 microM) for 1h and the DNA breakage was assessed using single cell alkaline gel electrophoresis (Comet assay). Inhibition of DNA breakage by several scavengers of reactive oxygen species (ROS) indicated that it is caused by the formation of ROS. Incubation of lymphocytes with neocuproine (a cell membrane permeable Cu(I) chelator) inhibited DNA degradation in intact lymphocytes in a dose dependent manner. Bathocuproine, which is unable to permeate through the cell membrane, did not cause such inhibition. We have further shown that delphinidin is able to degrade DNA in cell nuclei and that such DNA degradation is also inhibited by neocuproine suggesting that nuclear copper is mobilized in this reaction. These results indicate that the generation of ROS possibly occurs through mobilization of endogenous copper ions. The results are in support of our hypothesis that the prooxidant activity of plant polyphenols may be an important mechanism for their anticancer properties.     

Efficacy and safety of rituximab in patients with multiple sclerosis: An observational study at a tertiary center in Makkah,Saudi Arabia

Objectives:To assess the efficacy and safety of rituximab for multiple sclerosis (MS) treatment in terms of reduction in clinical relapses, magnetic resonance imaging (MRI) activity, Expanded Disability Status Scale (EDSS) score and adverse events.Methods:This is a retrospective cross-sectional study conducted at King Abdullah Medical City, from January 2017 to August 2021, involving patients with MS given rituximab, with 1-year follow-up. Clinical parameters were noted pre- and post-treatment to determine efficacy; adverse events were noted to analyze safety. A paired samples t-test was used to compare responses pre- and post-treatment. A p-value<0.05 was considered significant.Results:Among 31 patients, 6 (19.4%) had progressive MS, and 25 (80.6%) had relapsing-remitting MS (mean disease duration=8.12±5.65 years). The annual relapse rate reduced from 1.67±0.97 to 0.06±0.25 (p<0.001), the EDSS score from 3.16±2.14 to 2.80±2.28 (p=0.141) and the MRI activity score from 1.84±1.03 to 1.03±0.18 (p<0.001). Only one patient had enhancing lesion activity post-treatment. The commonest side effect was urinary tract infection (25.8%). Only 2 patients discontinued the drug.Conclusion:Rituximab is an efficient drug in reducing the annual relapse rate and MRI activity of patients with MS, with few tolerable side effects not leading to drug discontinuation or any lethal outcome.

Multiple sclerosis (MS) is a condition of the central nervous system carrying a chronic course and having autoimmune etiology. The disease has a prevalence of 40.4 per 100,000 people in Saudi Arabia. ¹ MS can have a relapsing-remitting course which begins with an acute attack and is then followed by full or partial recovery (also known as relapsing-remitting MS [RRMS]). Alternative clinical presentation of MS is characterized by progressive neurological worsening without any acute attack (also known as primary progressive MS). Secondary Progressive MS is another advanced stage in the course of disease where disability worsens gradually without a new relapse. ^2,3 The disease process was earlier thought to be mediated by T cells, but research has brought forth the suggestion that B cells, too, do play a role in the pathological process. ⁴ It is now well understood that antigen presentation by B cells is a necessary step in the pathogenesis of the immune-mediated process against the glycoprotein myelin found in central nervous system. ⁵ Therapies targeting T cells (for example, interferon-beta and natalizumab) have been traditionally used for MS, but not all patients improve despite treatment compliance. Moreover, interferon causes a myriad of highly stressful side effects, and natalizumab, in addition to causing minor adverse effects, has a risk of causing a serious condition like progressive multifocal leukoencephalopathy (PML). ⁶ New therapies that target B cells are increasingly being investigated. Rituximab (RTX) is one such drug that targets CD 20 expressing B cells and also reduces T cells. The drug has shown promising results in the treatment process. ^7,8 The safety of RTX usage is established by Class IV evidence. ⁹ Phase 2 trials have shown that RTX reduces magnetic resonance imaging (MRI) inflammatory lesions by up to 88% in the patients of MS. ^10,11 Off-label RTX usage in MS is further supported by several trials. ^11,12,13 One such study showed MRI activity reduce from 88% to 8.3% in only a year and annual relapse rate reduce from 0.75 to 0.36 with the use of RTX. ¹³ The common side effects of RTX usage in patients with MS include infections (36%), with urinary tract infection being the most common, and infusion reactions (8%). This CD 20 targeting drug also increases the risk for fungal infections. ^14,15 Studies comparing the efficacy of RTX to conventional therapies have concluded that RTX has better performance in MS, especially in newly diagnosed cases of RRMS. ¹⁶ Our aim was to study the reduction in MRI inflammatory lesions, disability changes and relapses in patients with MS presenting at King Abdullah Medical City as a result of RTX therapy.     

Association between precystectomy epithelial tumor marker response to neoadjuvant chemotherapy and oncological outcomes in urothelial bladder cancer

Introduction and Objectives

We previously reported that elevated precystectomy serum levels of epithelial tumor markers predict worse oncological outcome in patients with invasive bladder cancer (BC). Herein, we evaluated the effect of neoadjuvant chemotherapy (NAC) on elevated tumor marker levels and their association with oncological outcomes.