Schofieldkrogsgaard6540

Biliary tract cancer (BTC), which includes cholangiocarcinoma and gallbladder carcinoma, is a rare malignancy. Due to its low incidence, drugs treating these diseases are scarce, so they can be considered orphan drugs. The main treatment choice for BTC is chemotherapy with gemcitabine or cisplatin or combined use of both, but patients fail to significantly benefit from established chemotherapy. Advancements in immunotherapy and targeted therapy will shed light on ways to improve clinical outcomes for patients with BTC. In conjunction, more new drugs will come onto the market. This article compares the conditions for development of orphan drugs in different countries and it describes several types of new drugs that were recently approved to treat BTC.Hereditary angioedema due to C1-inhibitor (C1-INH) deficiency (HAE-C1-INH) induces an acute attack of angioedema. In 2018, icatibant available for self-possession and subcutaneous self-administration was licensed for on-demand treatment in addition to intravenous C1-INH administration in Japan. We retrospectively evaluated the percentage of attacks in critical parts at emergency room (ER) visits and the time until visiting ER for C1-INH administration before and after the initial prescription of icatibant. The percentage of attacks in critical parts at ER visits before the prescription was 69.2%, but that was 80.0% when patients visited ER for additional C1-INH administration after the self-administration of icatibant. The time from the onset of an acute attack to visiting ER for the additional treatment after the self-administration of icatibant significantly increased from 6.2 h to 19.2 h (p less then 0.001). Icatibant, therefore, promoted the patients' behavior modification associated with ER visits for C1-INH administration during an acute attack of HAE-C1-INH.Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition with soft tissue progressive ossification, leading to severe disability. We describe a 27-years-old female affected by FOP who died after a fall. An autopsy was performed. Upper and lower extremities resulted in fixed flexion, with kyphoscoliosis of the spine and chest wall deformity. Moreover, a cranial fracture was pointed out. At histology, atypical abundance of corpora amylacea in gray matter was observed. In a sample of macroscopically non-affected muscular tissue, small areas with necrosis of myocytes and hyperplasia of fibroblasts were seen in light microscopy, with intracellular inorganic dystrophic inclusions in transmission electron microscopy. Thyroid gland histology showed diffuse lymphocytic infiltration. Postmortem examination of FOP patients provided precious information about involvement of other tissues, suggesting an initial and widespread inflammatory/dystrophic phase, to be further investigated, because it might reveal new insights about a FOP mutation cascade.The synchronous occurrence of primary breast cancer and lymphoid tissue malignant tumors has been rarely reported in the literature. We present an exceedingly rare case of synchronous breast invasive ductal carcinoma with an abdominal diffuse large B-cell lymphoma (DLBCL). A 78-year-old woman who was diagnosed with a luminal A invasive breast cancer on core biopsy, and complaint of progressively worsening low back pain. An abdominal computed tomography (CT) scan that was performed as part of the preoperative staging showed a large abdominal mass measuring 10.5 × 4.8 × 9.5 cm surrounding the lower part of the abdominal aorta, the right common iliac, right external, right internal iliac, and the left internal iliac arteries. A CT-guided fine-needle aspiration biopsy (FNAB) of the abdominal mass was then performed, to exclude the possibility of being an abdominal tumor metastasis of the known primary breast cancer. Histopathological findings were suggestive of DLBCL. Following a multidisciplinary team discussion, chemotherapy was initiated for DLBCL. The tumor however was refractory to multiple chemotherapy regimens and exhibited a highly aggressive clinical course. The diagnostic evaluation and management of the patient are discussed, along with a review of the relevant literature. This case underscores the fact that the presence of synchronous malignancies may pose both diagnostic and treatment challenges. Accurate staging of both malignancies and multidisciplinary team discussion is of utmost importance to guide an optimal therapeutic approach. Histopathological evaluation is essential for both tumors, for the second malignancy not to be misinterpreted as a secondary deposit of the primary one.We report a case of saccharopinuria with hyperammonemia and hypercitrullinemia in a Japanese woman who presented with elderly-onset epilepsy, progressive cognitive decline, and gait ataxia. Blood amino acid analysis revealed an increase in citrulline, cystine, and lysine levels, and urine amino acid analysis showed increased citrulline and cystine levels. Urine metabolomics revealed an increased saccharopine level, leading to the definitive diagnosis of saccharopinuria. In western blots of liver biopsy samples, normal citrin levels were observed, suggesting that adult-onset citrullinemia type 2 (CTLN2) was not present. In addition, decreased argininosuccinate synthetase (ASS) levels were observed, and ASS1 gene, a causative gene for citrullinemia type 1 (CTLN1), was analyzed, but no gene mutations were found. Because the causes of hypercitrullinemia were not clear, it might be secondary to saccharopinuria. Muscle biopsy findings of the biceps brachii revealed diminished cytochrome c oxidase (COX) activity, mitochondrial abnormalities on electron microscopy and p62- positive structures in immunohistochemical analyses. Saccharopinuria is generally considered a benign metabolic variant, but our case showed elevated lysine and saccharopine levels causing ornithine circuit damage, mitochondrial dysfunction, and autophagy disorders. This may lead to so far unknown neurological disorders.Immunosuppression is the cornerstone therapy for anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) myopathy. Typical immunosuppressants such as corticosteroids, methotrexate, and azathioprine have been used in conjunction with removal of the offending agent, yet the use of rituximab is more limited in this type of myopathy. Reported here is a case of a patient who responded well to rituximab (RTX) after the standard immunosuppressants had failed. This case illustrates the importance of further studies to evaluate the role of RTX in anti-HMGCR myopathy.Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by hypersensitivity of the skin to ultraviolet radiation and other carcinogenic agents. This ailment is characterized by increased photosensitivity, skin xerosis, early skin aging, actinic keratosis, erythematous lesions, and hyperpigmentation macules. In this serial case report, we presented four cases with XP from two families in Indonesia. Both families were referred from rural referral health centers, and each family has two affected siblings. They had freckle-like pigmentation on the face, trunk, and extremities, which progressed since childhood. One patient of family 2 died because of an infectious disease. Histopathological examination using cytokeratine (CK), CD10, and Ber-EP4 staining from available tissue biopsy of one affected case of family 1 identified basal cell carcinoma (BCC) on the cheek and melanoma on the right eye. Mutation analysis found ERCC2, c2047C>T and XPC, c1941T>A in the first and second families, respectively. We suppose that this is the first case report of XP in Indonesia that incorporates clinical examination, genetic analysis, and extensive histopathological examination, including immunohistochemistry staining, and a novel pathogenic variant of XPC was found in the second family.Muscle-bone interaction might regulate bone remodeling in an endocrine manner, but the exact mediators have not been identified. Previous in vitro studies suggest that exosomal miRNAs are a candidate for this interaction. Here we present an in vivo study to show that targeted knockout of a muscle-specific miR-23a cluster including miR-23a, miR-27, and miR-24-2 in skeletal muscle tissues can suppress bone remodeling in mice. The effect of miR-23a cluster seem to not be related to aging, but can worsen the pathological extent of osteoporosis in mice. Our findings suggest that muscle-derived miRNAs may contribute to bone metabolism regulation through exosomes in muscle-bone interaction.The bicaudal D homolog 2 (BICD2) gene encodes a protein required for the stable complex of dynein and dynactin, which functions as a motor protein working along the microtubule cytoskeleton. Both inherited and de novo variants of BICD2 are reported with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). Here, we report a male patient with a novel mutation in the BICD2 gene caused by a heterozygous substitution of arginine with cysteine at residue 162 (Arg162Cys); inherited from his asymptomatic mother. The patient showed typical clinical symptoms of SMALED2, which was genetically confirmed by sequencing. The Arg162Cys mutant clusters with four previously reported variants (c.361C>G, p.Leu121Val; c.581A>G, p.Gln194Arg; c.320C>T, p.Ser107Leu; c.565A>T, p.Ile189Phe) in a region that binds to the dynein-dynactin complex (DDC). Androgen Receptor Antagonist The BICD2 domain structures were predicted and the Arg162Cys mutation was localized in the N-terminus coiled-coil segment 1 (CC1) domain. Protein modeling of BICD2's CC1 domain predicted that the Arg162Cys missense variant disrupted interactions with dynein cytoplasmic 1 heavy chain 1 within the DDC. The mutant did this by either changing the electrostatic surface potential or making a broader hydrophobic unit with the neighboring residues. This hereditary case supports the complex and broad genotype-phenotype correlation of BICD2 mutations, which could be explained by incomplete penetrance or variable expressivity in the next generation.EAST/SeSAME syndrome is a rare disease affecting the Central Nervous System (CNS), inner ear, and kidney. The syndrome is due to loss-of-function mutations in the KCNJ10 gene encoding the inward-rectifying potassium channel Kir4.1. EAST/SeSAME syndrome is mainly diagnosed during childhood with a tonic-clonic seizure being the usual first symptom. Due to a limited number of patients and recent identification of the disease, few data are available on the clinical progress of this disease in adulthood. In particular, neurologic and nephrological outcomes have not been reported. We present a case series of 4 adult patients harbouring homozygous missense mutation p.Ala167Val and homozygous frameshift mutations p.Asn232Glnfs*14 and p.Gly275Valfs*7. Effects of these mutations were predicted by in silico modelling and bioinformatic tools. Patients with truncating mutations were associated with more severe outcomes, both in tubulopathy severity and neurological symptomatology. Conversely, either missense or truncating mutations were correlated with similar severity of epilepsy, with a long free-of-event period up to 20 years old. No eGFR decline was documented. Modelling predicted that truncating mutations lead to complete Kir4.1 dysfunction. Finally, all patients had a mild increase in urinary protein excretion. Our study indicates that the prognosis of patients suffering from EAST/SeSAME syndrome is related to the severity of the mutation causing the disease. As predicted by in silico modelling, truncating mutations of KCNJ10 are associated with more severe disease, with recurrence of symptomatic hypokalemia and more severe neurological phenotype. The type of mutation should be considered for the therapy tailored to patients' phenotype.