Krausewilloughby6897

Although BRAF inhibition has demonstrated activity in BRAF V600 -mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAF V600 -mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated.T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/T ALL) is an aggressive hematological malignancy arising from malignant transformation of T-cell progenitors with poor prognosis in adult patients. Outcomes are particularly dismal in the relapsed/refractory setting, and therapeutic options are limited in this context. Genomic profiling has shown frequent aberrations in the JAK-STAT pathway, including recurrent mutations in JAK3 (15%-20% of T-ALL cases), suggesting that JAK kinase inhibition may be a promising therapeutic approach. Activating JAK3 mutations are capable of transforming cytokine-dependent progenitor cells in vitro and causing T-ALL-like disease when expressed in hematopoietic progenitors in vivo. We describe a case of relapsed T-ALL in an adult patient, with two JAK3 activating mutations identified by whole-exome sequencing (WES), leading to hypothesis-based treatment with the JAK1 and JAK3 inhibitor, tofacitinib, following failure of salvage chemotherapy reinduction. Despite the molecularly targeted rationale, tofacitinib did not induce an objective clinical response. Our report suggests that the presence of activating JAK3 mutations does not necessarily confer sensitivity to pharmacological JAK3 inhibition.Commentary by Dr James Kimpton and Dr Teck Khong Clinical Pharmacology, St George's, University of London, UKSeries Editor Dr Teck Khong, DTB Associate Editor Clinical Pharmacology, St George's, University of London, UKCommentary on Kraus WE, Bhapkar M, Huffman KM, et al 2 years of calorie restriction and cardiometabolic (CALERIE) exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol 2019; 7 673-83.The aim of this review is to explain why the term 'desquamative interstitial pneumonia' (DIP) should be discarded and replaced with modern terminology. Reason 1 DIP is a misnomer. Within a few years after the term was coined, it was shown that the airspace cells in DIP are macrophages not desquamated pneumocytes. Reason 2 As a result of overly simplistic and poorly defined histologic criteria, DIP is currently a mixed bag of smoking-related diseases and unrelated processes in never-smokers. Reason 3 DIP obfuscates the modern concept that smoking causes some forms of parenchymal lung disease. Despite the fact that >80% of cases of DIP are caused by smoking, it is currently classified as a 'smoking-related idiopathic interstitial pneumonia', an oxymoron. Reason 4 The premise that the presence of numerous macrophages within airspaces defines an entity creates problematic histologic overlap with other lung diseases that may feature prominent airspace macrophages. Reason 5 DIP is outdated. It was coined in 1965, when many entities in interstitial lung disease had not been described, smoking-related interstitial lung disease was an unknown concept, computed tomograms of the chest had not been introduced and immunohistochemistry was unavailable. We suggest a way forward, which includes eliminating the term DIP and separating smoking-related lung abnormalities (including accumulation of pigmented airspace macrophages) from cases characterised by numerous non-pigmented macrophages in never-smokers. Dihydroartemisinin chemical structure The laudable goal of smoking cessation is not served well by muddying the relationship between smoking and lung disease with inaccurate, outdated terminology.A 44-year-old woman diagnosed with a HER2 positive early breast cancer, receiving neoadjuvant treatment with paclitaxel and targeted agents, trastuzumab together with pertuzumab, presented to the emergency room with gait instability and upper right limb weakness. The neurological examination was compatible with cerebellar alteration showing right dissymmetry of the finger-nose and heel-knee manoeuvre. A head CT and a brain MRI were performed and negative. The electromyography showed alterations of the pyramidal pathway and somatosensory pathway. In order to determine the cause of the cerebellar affection, a lumbar puncture was performed. The cerebrospinal fluid analysis was non-specific, but the antineuronal anti-Yo antibody was positive, being diagnosed of a paraneoplastic cerebellar degeneration (PCD). A positron emission tomography CT ruled out metastatic disease. The patient completed four cycles of antiHER2 blockade and weekly paclitaxel, achieving a complete pathological response. One year later, she maintains a complete remission but the PCD still prevails.An elderly woman underwent hardware removal and total joint replacement (TJR) of her right knee. Ipsilateral total tip replacement was performed 7 years earlier, and 12 months later, a supracondylar fracture of the index femur was successfully treated by open reduction internal fixation (ORIF) of the distal femur with a locking compression plate condylar plate. Hardware removal attempt, prior to the arthroplasty, resulted in fracture of the distal femur. Total knee replacement (TKR) was commenced with temporary reduction and final stabilisation of the femur fracture with a condylar plate. Postoperatively, non-union of the femur fracture developed twice with fatigue failure of the plate fixation device in both instances. Refixation of the femur was performed on both occasions and additional bone healing augmentation measures were performed for each subsequent surgery. Femur union was achieved fourteen months after the last surgery.Thalamic deep brain stimulation (DBS) for chronic pain is performed in selected patients with a variable success rate. We report the use of recently developed directional DBS in a patient with hemibody central poststroke pain (CPSP) and its added value in the induction of pleasant, pain-distracting paresthesia's throughout the contralateral body side. A 68-year-old man suffered from multiple strokes in the left hemisphere 11 years before presentation, resulting in medically refractory right-sided hemibody CPSP. He was implanted with a directional DBS electrode in the left ventrocaudal nucleus of the thalamus. A directional single-segment contact configuration produced a better improvement throughout the contralateral body side than ring-mode and other directional configurations. Treatment led to a reduction of almost 50% in pain. This case demonstrates the value of directional DBS in the treatment of chronic pain, as steering increases selectivity and reduces side effects in a small target area surrounded by structures with high functional diversity.A 19-year-old man presented with acute severe ulcerative colitis. He was taking azathioprine (therapeutic metabolites) and sulphasalazine as well as infliximab with a therapeutic drug level. On day 3 of hydrocortisone therapy, he met day Oxford criteria with >8 bloody stools per day and was given faecal microbiota transplantation and subsequently commenced on dietary therapy combining several strategies-(1) increased intake of fermentable fibres, (2) reduced intake of overall and sulfur-containing protein and (3) restriction of sulfate and sulfite food additives. At week 8 assessment, he was in clinical and endoscopic remission and remained in clinical and endoscopic remission at 12 months.Histoplasmosis is a systemic fungal infection caused by Histoplasma capsulatum, a dimorphic fungus that spreads commonly by contamination of soil with bird and bat droppings. The infection remains latent in most patients until manifested by reduced immune status, for example, HIV/AIDS, corticosteroid/immunosuppressive therapy or in solid organ transplant recipients. Tuberculosis and histoplasmosis may cooccur rarely in HIV and the clinical resemblance of both diseases may hinder identification of patients' harbouring dual infection, especially in regions non-endemic for histoplasmosis. link2 We report a case of disseminated histoplasmosis with disseminated tuberculosis in an incidentally detected patient with HIV-positive who presented with reports of fever and skin rash for 10 days. The Mantoux positivity and CT of chest and abdomen revealing multiple necrotic lymph nodes coupled with bone marrow and skin biopsy divulging histoplasmosis and tuberculosis helped us clinch the concurrent infection.The use of implants has enabled more treatment options for prosthetic rehabilitation of partially and completely edentulous patients. This clinical report describes a treatment approach for an 80-year-old patient taking advantage of the remaining natural teeth for prosthetic rehabilitation. The final treatment plan included natural tooth-supported and implant-supported crowns combined with a milled bar partial overdenture retained by tilted dental implants. The overdentures supported by the milled bar implants provide the advantages of both fixed and removable restorations. In addition to patient satisfaction, the overdentures also minimise alveolar bone resorption, increase longevity and stability and improve masticatory efficiency.Quinidine is one of the oldest antiarrhythmics known. Over the years, its use has decreased along with its side effects. Our case describes a 69-year-old woman with recurrent resistant ventricular tachycardia on Quinidine and Amiodarone who presented with acute liver toxicity. Drug-induced liver toxicity was at the top of our differential diagnosis list. link3 Taking multiple factors into consideration, a decision was made to discontinue Quinidine, the patient's symptoms and lab abnormalities resolved within 1 week, yielding the diagnosis of Quinidine hypersensitivity.We present a case of sudden asystole that was elicited via the trigeminocardiac reflex in a patient undergoing surgery for a frontal sinus fracture. Asystole occurred after mild stimulation of the supraorbital nerve during dissection along the superior orbital rim. Anticholinergics were administered and lidocaine-soaked gauze was applied to the exposed wound. The patient was an athlete and had pre-existing sinus bradycardia. We hypothesise that the severe reflex response was associated with his underlying increased vagal tone. When performing surgery in patients with increased vagal tone, preventative measures to diminish the trigeminocardiac reflex are recommended. Further studies are needed.Methaemoglobinaemia is a rare disease that is typically caused by a medication or other exogenous agent, with dapsone being the most common. It occurs when the concentration of methaemoglobin rises via ferrous haeme irons becoming oxidised to the ferric state, which shifts the oxygen dissociation curve to the left. The net result of an elevated methaemoglobin concentration is functional anaemia and impaired oxygen delivery to tissues. At lower blood levels, this can cause symptoms such as cyanosis, lethargy, headache and fatigue, whereas at higher levels it can be fatal. Here we discuss a subtle case of dapsone-induced methaemoglobinaemia presenting as subacute mental status changes and apparent hypoxia, thus highlighting the association between methaemoglobinaemia and dapsone. This case demonstrates the importance of thorough medication reconciliation and maintaining a broad differential diagnosis, while also recognising the significance of conflicting data and their implications for the workup.