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1.
Cancers (Basel) ; 16(13)2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-39001380

RESUMEN

Rectal cancer typically necessitates a combination of radiotherapy (RT), chemotherapy, and surgery. The associated functional disorders and reduction in quality of life have led to an increasing interest in organ preservation strategies. Response strongly correlates with RT dose, but dose escalation with external beam remains limited even with modern external beam RT techniques because of toxicity of the surrounding tissues. This study reports on the use of Papillon, an endocavitary Radiotherapy device, in the treatment of rectal cancer. The device delivers low energy X-rays, allowing for safe dose escalation and better complete response rate. Between January 2015 and February 2024, 24 rectal cancer patients were treated with the addition of a boost delivered by Papillon to standard RT, with or without chemotherapy, in an upfront organ preservation strategy. After a median follow-up (FU) of 43 months, the organ preservation rate was 96% (23/24), and the local relapse rate was 8% (2/24). None of our patients developed grade 3 or more toxicities. Our results demonstrate that the addition of Papillon contact RT provides a high rate of local remission with sustained long-term organ preservation, offering a promising alternative to traditional surgical approaches in patients with rectal cancer.

2.
Cancers (Basel) ; 15(17)2023 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-37686674

RESUMEN

BACKGROUND: Malnutrition, loss of weight and of skeletal muscle mass are frequent in pancreatic cancer patients, a majority of which will undergo chemotherapy over the course of their disease. Available data suggest a negative prognostic role of these changes in body composition on disease outcomes; however, it is unclear whether tolerance to chemotherapeutic treatment is similarly and/or negatively affected. We aimed to explore this association by retrospectively assessing changes in body composition and chemotherapy-related toxicity in a cohort of advanced pancreatic cancer patients. METHODS: Body composition was evaluated through clinical parameters and through radiological assessment of muscle mass, skeletal muscle area, skeletal muscle index and skeletal muscle density; and an assessment of fat distribution by subcutaneous adipose tissue and visceral adipose tissue. We performed descriptive statistics, pre/post chemotherapy comparisons and uni- and multivariate analyses to assess the relation between changes in body composition and toxicity. RESULTS: Toxicity risk increased with an increase of skeletal muscle index (OR: 1.03) and body mass index (OR: 1.07), whereas it decreased with an increase in skeletal muscle density (OR: 0.96). Multivariate analyses confirmed a reduction in the risk of toxicity only with an increase in skeletal muscle density (OR: 0.96). CONCLUSIONS: This study suggests that the retrospective analysis of changes in body composition is unlikely to be useful to predict toxicity to gemcitabine-nab-paclitaxel.

3.
Cancers (Basel) ; 14(22)2022 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-36428573

RESUMEN

Pancreatic neuroendocrine neoplasms (PanNENs) are the second most common malignancy of the pancreas. Surgery remains the only curative treatment for localized disease. For patients with inoperable advanced or metastatic disease, few targeted therapies are available, but their efficacy is unpredictable and variable. Exploiting prior knowledge on pathogenetic processes involved in PanNEN tumorigenesis, we tested buparlisib (PI3K inhibitor) and ribociclib (CDK4/6 inhibitor), as single agents or in combination, in different preclinical models. First, we used cell lines representative of well-differentiated (INS-1E, NT-3) and poorly differentiated (BON-1) PanNENs. The combination of buparlisib with ribociclib reduced the proliferation of 2D and 3D spheroid cultures more potently than the individual drugs. Buparlisib, but not ribociclib, induced apoptosis. The anti-proliferative activity of the drugs correlated with downstream target inhibition at mRNA and protein levels. We then tested the drugs on primary islet microtissues from a genetic PanNET animal model (Men1-defective mice) and from wild-type mice: the drug combination was effective against the former without altering islet cell physiology. Finally, we treated PanNET patient-derived islet-like 3D tumoroids: the combination of buparlisib with ribociclib was effective in three out of four samples. Combined targeting of PI3K and CDK4/6 is a promising strategy for PanNENs spanning various molecular and histo-pathological features.

4.
Curr Oncol ; 29(8): 5604-5615, 2022 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-36005180

RESUMEN

In Switzerland, physicians do not have national guidelines for metastatic colorectal cancer (mCRC) patient care and utilize international versions for management recommendations. Moreover, information about adherence to these guidelines and real-world practice patterns in Switzerland or other countries is lacking. The Screening and COnsensus based on Practices and Evidence (SCOPE) program were designed by an international expert panel of gastrointestinal oncologists to gather real-world insights in the current clinical setting to manage patients with mCRC who have received prior treatment. We sought to understand general practice patterns, the influence of molecular diagnostics (e.g., testing for KRAS, NRAS, BRAF, and MSI), tumor sidedness, and patient-centric factors on treatment selection utilizing in-person surveys and three hypothetical patient case scenarios. Here, we describe and evaluate the Swiss data from the SCOPE program within the context of an international viewpoint and discuss the findings of our analysis. In general, we find that the real-world clinical decisions of Swiss physicians (SWI) closely follow international (INT) recommendations and guidelines, largely paralleling their regional and international counterparts in using the two approved treatments in the third- and fourth-line settings, namely trifluridine-tipiracil and regorafenib. Finally, our data suggest a tendency toward the use of trifluridine-tipiracil (SWI: 79%; INT: 66%) over regorafenib (SWI: 18%; INT: 18%) as the preferred third-line treatment choice in mCRC patients regardless of KRAS status.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Consenso , Detección Precoz del Cáncer , Humanos , Proteínas Proto-Oncogénicas p21(ras) , Neoplasias del Recto/tratamiento farmacológico , Suiza , Trifluridina/uso terapéutico
5.
Oncol Res Treat ; 44(9): 485-494, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34350899

RESUMEN

BACKGROUND: Gastric cancer is a leading cause of cancer-related deaths worldwide. Several treatment possibilities have been investigated, but only a few show clinically meaningful results. SUMMARY: Systemic treatment options for advanced gastric cancer (aGC) have evolved over the recent years, implementing the growing molecular knowledge of this heterogeneous disease. Molecular profiling (at least for HER-2-expression, microsatellite instability status, Epstein-Barr virus expression, and programmed death ligand-1 expression/combined positive score [CPS]) is recommended for all therapy-fit patients prior to the start of a systemic treatment and is crucial for decisions on treatment strategy and drug selection. Various examples like the application of trastuzumab in the HER-2-positive subgroup underline the benefits of this approach starting from the first-line setting. A combination of platinum and fluoropyrimidine remains the first-line chemotherapy backbone in the treatment of advanced gastric cancer. Triplet combinations adding taxanes to the doublet regimen are reserved for certain scenarios. Unfortunately, almost all patients who receive first-line treatment (with or without anti-HER-2 blockade) progress and <70% are eligible for a second-line therapy. The addition of monoclonal antibodies has substantially improved outcomes in this setting. As such, ramucirumab has led to significant and clinically meaningful advancements in the second-line treatment. Furthermore, immuno-oncology with checkpoint inhibition and immune stimulation has evolved in the field of aGC. Recent first-line data show a significant survival benefit in aGC patients with a CPS ≥ 5 under immunochemotherapy. Nonetheless, the impact of immunotherapy combinations and immunochemotherapy remains an area of investigation. Key Message: In this review, we highlight recent improvements in the treatment landscape of advanced gastric cancer, the heterogeneity of this disease, and possible personalized targets.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Herpesvirus Humano 4 , Humanos , Oncogenes , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Suiza
6.
Medicine (Baltimore) ; 100(4): e24463, 2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33530256

RESUMEN

INTRODUCTION: Standardized systemic treatment options are lacking for carcinoma ex pleomorphic adenoma, which is a rare and aggressive tumor primarily found in salivary glands.Here we report the case of a 63-year-old male with carcinoma ex pleomorphic adenoma of the left parotid and parapharyngeal space harboring a neurotrophic receptor tyrosine kinase (NTRK) 2 fusion who was treated with a small molecule inhibitor that targets the tropomyosin receptor kinase (TRK) proteins. To the best of our knowledge, no similar case has been described in the literature so far. PATIENT CONCERNS: After multiple surgical resections and radiotherapy for localized cancer disease over several years, our patient again developed an increasing swelling and pain around the left ear and numbness of the left half of the face. DIAGNOSIS: Magnetic resonance imaging and positron emission tomography/computed tomography scans showed tumor recurrence in the left parotid, below the left ear, and in the parapharyngeal space, as well as metastases of the lungs and cervical lymph nodes. As data on the efficacy of systemic therapies for inoperable carcinoma ex pleomorphic adenoma are scarce, we performed a next-generation sequencing that revealed the presence of a hitherto unknown NTRK2 fusion. INTERVENTIONS: Treatment with the TRK inhibitor larotrectinib was initiated, which induced rapid symptom improvement. However, part of the tumor had to be removed shortly afterwards due to local progression. Molecular testing did not demonstrate any alterations accounting for resistance to larotrectinib, with maintenance of the NTRK2 fusion. OUTCOMES: Three months later, imaging confirmed mixed response. While the reason for this remains unknown, the patient is in good condition and continues to receive larotrectinib. CONCLUSION: It remains unclear why our patient showed mixed response to larotrectinib and further studies are needed to explore other possible mechanisms of resistance.


Asunto(s)
Adenoma Pleomórfico/tratamiento farmacológico , Neoplasias de la Parótida/tratamiento farmacológico , Neoplasias Faríngeas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adenoma Pleomórfico/genética , Adenoma Pleomórfico/cirugía , Resistencia a Antineoplásicos , Humanos , Masculino , Glicoproteínas de Membrana , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Parótida/genética , Neoplasias de la Parótida/cirugía , Neoplasias Faríngeas/genética , Neoplasias Faríngeas/patología , Receptor trkB
7.
J Inherit Metab Dis ; 44(2): 492-501, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33368311

RESUMEN

Loss-of-function mutations in the deoxyguanosine kinase (DGUOK) gene result in a mitochondrial DNA (mtDNA) depletion syndrome. DGUOK plays an important role in converting deoxyribonucleosides to deoxyribonucleoside monophosphates via the salvage pathway for mtDNA synthesis. DGUOK deficiency manifests predominantly in the liver; the most common cause of death is liver failure within the first year of life and no therapeutic options are currently available. in vitro supplementation with deoxyguanosine or deoxyguanosine monophosphate (dGMP) were reported to rescue mtDNA depletion in DGUOK-deficient, patient-derived fibroblasts and myoblasts. CERC-913, a novel ProTide prodrug of dGMP, was designed to bypass defective DGUOK while improving permeability and stability relative to nucleoside monophosphates. To evaluate CERC-913 for its ability to rescue mtDNA depletion, we developed a primary hepatocyte culture model using liver tissue from DGUOK-deficient rats. DGUOK knockout rat hepatocyte cultures exhibit severely reduced mtDNA copy number (~10%) relative to wild type by qPCR and mtDNA content remains stable for up to 8 days in culture. CERC-913 increased mtDNA content in DGUOK-deficient hepatocytes up to 2.4-fold after 4 days of treatment in a dose-dependent fashion, which was significantly more effective than dGMP at similar concentrations. These early results suggest primary hepatocyte culture is a useful model for the study of mtDNA depletion syndromes and that CERC-913 treatment can improve mtDNA content in this model.


Asunto(s)
ADN Mitocondrial/genética , Mitocondrias/genética , Nucleótidos/farmacología , Fosfotransferasas (Aceptor de Grupo Alcohol)/deficiencia , Animales , Células CACO-2 , Variaciones en el Número de Copia de ADN , ADN Mitocondrial/efectos de los fármacos , Femenino , Hepatocitos/metabolismo , Humanos , Masculino , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Mutación , Nucleótidos/metabolismo , Profármacos/farmacología , Ratas , Ratas Transgénicas
8.
Oncogene ; 39(1): 164-175, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31462712

RESUMEN

Citrin, encoded by SLC25A13 gene, is an inner mitochondrial transporter that is part of the malate-aspartate shuttle, which regulates the NAD+/NADH ratio between the cytosol and mitochondria. Citrullinemia type II (CTLN-II) is an inherited disorder caused by germline mutations in SLC25A13, manifesting clinically in growth failure that can be alleviated by dietary restriction of carbohydrates. The association of citrin with glycolysis and NAD+/NADH ratio led us to hypothesize that it may play a role in carcinogenesis. Indeed, we find that citrin is upregulated in multiple cancer types and is essential for supplementing NAD+ for glycolysis and NADH for oxidative phosphorylation. Consequently, citrin deficiency associates with autophagy, whereas its overexpression in cancer cells increases energy production and cancer invasion. Furthermore, based on the human deleterious mutations in citrin, we found a potential inhibitor of citrin that restricts cancerous phenotypes in cells. Collectively, our findings suggest that targeting citrin may be of benefit for cancer therapy.


Asunto(s)
Carcinogénesis/genética , Mitocondrias/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Neoplasias/genética , Carbohidratos/genética , Citrulinemia/genética , Citrulinemia/metabolismo , Citosol/metabolismo , Citosol/patología , Regulación Neoplásica de la Expresión Génica/genética , Mutación de Línea Germinal/genética , Glutamatos/farmacología , Ácido Glutámico/análogos & derivados , Ácido Glutámico/farmacología , Glucólisis/genética , Humanos , Mitocondrias/metabolismo , Mitocondrias/patología , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fosforilación Oxidativa/efectos de los fármacos
9.
J Immunother ; 42(7): 274-277, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31219972

RESUMEN

Mixed adenoneuroendocrine carcinoma (MANEC) is a rare, aggressive tumor arising from different localizations along the gastrointestinal tract with generally poor prognosis. We present the case of a 51-year-old female patient with histopathologically confirmed diagnosis of a MANEC of the descending colon. At presentation, the tumor had already spread to the liver causing extensive hepatic metastases. Immunohistochemical examination showed 5%-10% of tumor cells to express the programmed cell death receptor ligand 1 and FoundationOne testing revealed a high mutational tumor burden with 149 Muts/Mb. The patient responded very well clinically and radiologically to anti-programmed death 1 receptor monoclonal antibody pembrolizumab therapy after having undergone 3 previous systemic treatment regimens as well as selective internal radiation therapy of her hepatic metastases. Clinical improvement was evident after the first infusion already and is ongoing for 10 months so far with very little side effects including initial and short lived skin irritation as well as muscle pain. To our knowledge, this is the first published case where a MANEC was successfully treated with immunotherapy targeting the programmed death 1 receptor.


Asunto(s)
Adenocarcinoma/diagnóstico , Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma Neuroendocrino/diagnóstico , Carcinoma Neuroendocrino/tratamiento farmacológico , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/tratamiento farmacológico , Adenocarcinoma/etiología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Biopsia , Carcinoma Neuroendocrino/etiología , Neoplasias del Colon/etiología , Terapia Combinada , Femenino , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Persona de Mediana Edad , Terapia Molecular Dirigida , Metástasis de la Neoplasia , Estadificación de Neoplasias , Resultado del Tratamiento
10.
Hum Mol Genet ; 28(17): 2937-2951, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31152168

RESUMEN

KCNMA1 encodes the large-conductance Ca2+- and voltage-activated K+ (BK) potassium channel α-subunit, and pathogenic gain-of-function variants in this gene have been associated with a dominant form of generalized epilepsy and paroxysmal dyskinesia. Here, we genetically and functionally characterize eight novel loss-of-function (LoF) variants of KCNMA1. Genome or exome sequencing and the participation in the international Matchmaker Exchange effort allowed for the identification of novel KCNMA1 variants. Patch clamping was used to assess functionality of mutant BK channels. The KCNMA1 variants p.(Ser351Tyr), p.(Gly356Arg), p.(Gly375Arg), p.(Asn449fs) and p.(Ile663Val) abolished the BK current, whereas p.(Cys413Tyr) and p.(Pro805Leu) reduced the BK current amplitude and shifted the activation curves toward positive potentials. The p.(Asp984Asn) variant reduced the current amplitude without affecting kinetics. A phenotypic analysis of the patients carrying the recurrent p.(Gly375Arg) de novo missense LoF variant revealed a novel syndromic neurodevelopmental disorder associated with severe developmental delay, visceral and cardiac malformations, connective tissue presentations with arterial involvement, bone dysplasia and characteristic dysmorphic features. Patients with other LoF variants presented with neurological and developmental symptoms including developmental delay, intellectual disability, ataxia, axial hypotonia, cerebral atrophy and speech delay/apraxia/dysarthria. Therefore, LoF KCNMA1 variants are associated with a new syndrome characterized by a broad spectrum of neurological phenotypes and developmental disorders. LoF variants of KCNMA1 cause a new syndrome distinctly different from gain-of-function variants in the same gene.


Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/genética , Mutación con Pérdida de Función , Fenotipo , Alelos , Sustitución de Aminoácidos , Fenómenos Electrofisiológicos , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Recién Nacido , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/química , Masculino , Mutación Missense , Linaje , Dominios Proteicos , Dominios y Motivos de Interacción de Proteínas
11.
J Neuropathol Exp Neurol ; 78(3): 283-287, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30715496

RESUMEN

The phenotypes associated with pathogenic variants in the ryanodine receptor 1 gene (RYR1, OMIM# 180901) have greatly expanded over the last few decades as genetic testing for RYR1 variants has become more common. Initially described in association with malignant hyperthermia, pathogenic variants in RYR1 are typically associated with core pathology in muscle biopsies (central core disease or multiminicore disease) and symptomatic myopathies with symptoms ranging from mild weakness to perinatal lethality. We describe a 2-week-old male patient with multiple congenital dysmorphisms, severe perinatal weakness, and subsequent demise, whose histopathology on autopsy was consistent with congenital muscular dystrophy. Immunohistochemical analysis of dystrophy-associated proteins was normal. Rapid exome sequencing revealed a novel heterozygous nonsense variant (p.Trp661Ter) in RYR1, as well as a previously described RYR1 pathogenic variant associated with congenital myopathy (p.Phe4976Leu). This highlights the potential for RYR1 pathogenic variants to produce pathological findings most consistent with congenital muscular dystrophy.


Asunto(s)
Enfermedades Musculares/genética , Enfermedades Musculares/patología , Distrofias Musculares/genética , Distrofias Musculares/patología , Canal Liberador de Calcio Receptor de Rianodina/genética , Índice de Severidad de la Enfermedad , Resultado Fatal , Humanos , Recién Nacido , Masculino
12.
J Geriatr Oncol ; 10(2): 304-310, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30559073

RESUMEN

INTRODUCTION: While the anti-VEGF antibody bevacizumab was studied repeatedly as part of low-intensity regimens in less fit elderly patients with metastatic colorectal cancer (mCRC), anti-EGFR antibodies as upfront treatment modality have been scarcely investigated. MATERIAL AND METHODS: In SAKK 41/10, the benefit of cetuximab, either alone or in combination with capecitabine, was evaluated in vulnerable elderly patients with RAS/BRAF-wild-type mCRC. RESULTS AND DISCUSSION: The trial was stopped prematurely due to slow accrual after the inclusion of 24 patients (11 in the monotherapy arm, 13 in the combination arm). Median patient age was 80 years (range 71-89), median CIRS-G score 7 (range 2-13), and median IADL score 7 (range 3-8). At week 12, 6 of 11 patients (55%) were progression-free in the cetuximab monotherapy arm and 9 of 13 patients (69%) in the combination arm. Response rate was 9% in the monotherapy arm and 38% combination arm. The 6 patients with right-sided primary tumors were not responsive to cetuximab. NGS revealed additional mutations affecting the RAS/RAF/MAP kinase pathway in 5 patients; 4 of these patients showed early disease progression. Cetuximab was generally well tolerated and a trend toward an improvement of symptom-related QoL was observed. In the combination arm, a higher incidence of toxicities and treatment stoppings was observed. In conclusion, trial recruitment - requiring both geriatric as well as molecular eligibility criteria - proved more difficult than expected. Bearing in mind the very small sample size, upfront cetuximab treatment appeared tolerable and showed promising activity in left-sided tumors in both treatment arms.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Capecitabina/administración & dosificación , Carcinoma/secundario , Cetuximab/administración & dosificación , Cetuximab/uso terapéutico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Terminación Anticipada de los Ensayos Clínicos , Femenino , GTP Fosfohidrolasas/genética , Humanos , Neoplasias Hepáticas/secundario , Masculino , Proteínas de la Membrana/genética , Metástasis de la Neoplasia , Selección de Paciente , Supervivencia sin Progresión , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética
13.
Cell ; 174(6): 1559-1570.e22, 2018 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-30100185

RESUMEN

The urea cycle (UC) is the main pathway by which mammals dispose of waste nitrogen. We find that specific alterations in the expression of most UC enzymes occur in many tumors, leading to a general metabolic hallmark termed "UC dysregulation" (UCD). UCD elicits nitrogen diversion toward carbamoyl-phosphate synthetase2, aspartate transcarbamylase, and dihydrooratase (CAD) activation and enhances pyrimidine synthesis, resulting in detectable changes in nitrogen metabolites in both patient tumors and their bio-fluids. The accompanying excess of pyrimidine versus purine nucleotides results in a genomic signature consisting of transversion mutations at the DNA, RNA, and protein levels. This mutational bias is associated with increased numbers of hydrophobic tumor antigens and a better response to immune checkpoint inhibitors independent of mutational load. Taken together, our findings demonstrate that UCD is a common feature of tumors that profoundly affects carcinogenesis, mutagenesis, and immunotherapy response.


Asunto(s)
Genómica , Metabolómica , Neoplasias/patología , Urea/metabolismo , Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Animales , Aspartato Carbamoiltransferasa/genética , Aspartato Carbamoiltransferasa/metabolismo , Carbamoil-Fosfato Sintasa (Glutamina-Hidrolizante)/genética , Carbamoil-Fosfato Sintasa (Glutamina-Hidrolizante)/metabolismo , Línea Celular Tumoral , Dihidroorotasa/genética , Dihidroorotasa/metabolismo , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Proteínas de Transporte de Membrana Mitocondrial , Neoplasias/metabolismo , Ornitina Carbamoiltransferasa/antagonistas & inhibidores , Ornitina Carbamoiltransferasa/genética , Ornitina Carbamoiltransferasa/metabolismo , Fosforilación/efectos de los fármacos , Pirimidinas/biosíntesis , Pirimidinas/química , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo
14.
J Neuropathol Exp Neurol ; 77(8): 665-672, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29850869

RESUMEN

Mitochondrial diseases (MDs) result from alteration of the mitochondrial respiratory chain (MRC) function. Despite the prevalence of MDs in the population, the paucity of animal models available limits the understanding of these disorders. Mutations in SDHA, a gene that codes for the alpha subunit of succinate dehydrogenase (SDH), can cause some forms of MD. SDHA is a crucial contributor to MRC function. In order to expand the range of MD animal models available, we attempted to generate a Sdha knockout rat. Since homozygous Sdha-/- rats could neither be identified in newborn litters, nor as early as embryonic day 14, we evaluated wild-type (WT) and heterozygous Sdha+/- genotypes. No differences in behavioral, biochemical, or molecular evaluations were observed between WT and Sdha+/- rats at 6 weeks or 6 months of age. However, 30% of Sdha+/- rats displayed mild muscle fiber atrophy with rare fibers negative for cytochrome oxidase and SDH on histochemical staining. Collectively, our data provide additional evidence that modeling SDH mutations in rodents may be challenging due to animal viability, and heterozygous rats are insufficiently symptomatic at a phenotypic and molecular level to be of significant use in the study of SDH deficiency.


Asunto(s)
Complejo II de Transporte de Electrones/genética , Complejo II de Transporte de Electrones/metabolismo , Fuerza de la Mano/fisiología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Animales , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Complejo II de Transporte de Electrones/análisis , Técnicas de Inactivación de Genes/métodos , Masculino , Músculo Esquelético/química , Ratas , Ratas Transgénicas
15.
Am J Med Genet A ; 176(3): 692-698, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29388319

RESUMEN

Mitochondrial NAD kinase deficiency (NADK2D, OMIM #615787) is a rare autosomal recessive disorder of NADPH biosynthesis that can cause hyperlysinemia and dienoyl-CoA reductase deficiency (DECRD, OMIM #616034). NADK2 deficiency has been reported in only three unrelated patients. Two had severe, unremitting disease; one died at 4 months and the other at 5 years of age. The third was a 10 year old female with CNS anomalies, ataxia, and incoordination. In two cases mutations in NADK2 have been demonstrated. Here, we report the fourth known case, a 15 year old female with normal intelligence and a mild clinical and biochemical phenotype presumably without DECRD. Her clinical symptoms, which are now stable, became evident at the age of 9 with the onset of decreased visual acuity, bilateral optic atrophy, nystagmus, episodic lower extremity weakness, peripheral neuropathy, and gait abnormalities. Plasma amino acid levels were within normal limits except for mean lysine and proline levels that were 3.7 and 2.5 times the upper limits of normal. Whole exome sequencing (WES) revealed homozygosity for a g.36241900 A>G p. Met1Val start loss mutation in the primary NADK2 transcript (NM_001085411.1) encoding the 442 amino acid isoform. This presumed hypomorphic mutation has not been previously reported and is absent from the v1000GP, EVS, and ExAC databases. Our patient's normal intelligence and stable disease expands the clinical heterogeneity and the prognosis associated with NADK2 deficiency. Our findings also clarify the mechanism underlying NADK2 deficiency and suggest that this disease should be ruled out in cases of hyperlysinemia, especially those with visual loss, and neurological phenotypes.


Asunto(s)
Genes Mitocondriales , Estudios de Asociación Genética , Proteínas Mitocondriales/deficiencia , Proteínas Mitocondriales/genética , Mutación , Fenotipo , Fosfotransferasas (Aceptor de Grupo Alcohol)/deficiencia , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Adolescente , Alelos , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Biomarcadores , Encéfalo/patología , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Proteínas Mitocondriales/química , Proteínas Mitocondriales/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/química , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo
16.
J Evid Based Med ; 10(4): 245-254, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28891275

RESUMEN

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and its incidence has increased during the past decade. While hepatitis B and C virus infections and alcohol were established risk factors, the impact of smoking on the incidence and mortality of HCC was needed to be confirmed. METHODS: We reviewed cohort and case-control studies evaluating the association between cigarette smoking and incidence and mortality of HCC from MEDLINE and Google Scholar. We also checked reference lists of original studies and review articles manually for cross-references up to February 2016. We extracted the relevant information on participant characteristics and study outcomes, as well as information on the methodology of the studies. We also assessed the quality of the included trials using critical appraisal skills program checklists. Meta-analysis was performed by using RevMan 5.3 software. RESULTS: A total of 81 studies were included in the systematic review. Pooled OR for HCC development with current smokers was 1.55 (95% CI: 1.46 to 1.65; P < 0.00001). Pooled OR for HCC development with former smokers was 1.39 (95% CI: 1.26 to 1.52; P < 0.00001) and pooled OR for HCC development with heavy smokers was 1.90 (95% CI: 1.68 to 2.14; P < 0.00001). Pooled OR for the mortality of current smokers with HCC was 1.29 (95% CI: 1.23 to 1.34; P < 0.00001); and for former smokers with HCC, it was 1.20 (95% CI: 1.00 to 1.42; P = 0.04). CONCLUSIONS: Cigarette smoking increases the incidence and mortality of HCC. Further studies are needed to evaluate possible impact of quitting smoking on decreasing this risk.


Asunto(s)
Carcinoma Hepatocelular/epidemiología , Fumar Cigarrillos , Neoplasias Hepáticas/epidemiología , Carcinoma Hepatocelular/mortalidad , Medicina Basada en la Evidencia , Humanos , Incidencia , Neoplasias Hepáticas/mortalidad , Factores de Riesgo
17.
Expert Rev Gastroenterol Hepatol ; 11(9): 865-869, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28697656

RESUMEN

BACKGROUND: Population-based data on the development of second malignant neoplasms (SMNs) following the diagnosis of hepatocellular carcinoma (HCC) are uncommon. We evaluated this clinical vignette in HCC patients within the Surveillance, Epidemiology and End Results (SEER) database. METHODS: The SEER database (1973-2012) was queried using the SEER*Stat program to determine the clinico-pathological features of HCC patients with more than one year survival who developed SMNs. Standardized incidence ratios (SIRs) were calculated to determine the risk of each type of subsequent cancers. Relative risk was assessed to determine the impact of liver transplantation on the development of second malignant neoplasms. RESULTS: On SIR analysis, the following sites have an enhanced risk of developing an SMN following the diagnosis of HCC: tongue, anal canal, liver, lung, kidney, thyroid, non-Hodgkin lymphoma (both nodal and extra-nodal disease) and acute monocytic leukemia (P < 0.05 for all sites). A significantly higher RR was found for the development of lung cancer (RR = 2.096), thyroid cancer (RR = 3.045) and non-Hodgkin lymphoma (RR = 3.822) among patients who underwent liver transplantation compared to those who did not (P < 0.05). CONCLUSION: There is an excess risk for developing a number of SMNs among patients diagnosed with HCC.


Asunto(s)
Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/efectos adversos , Anciano , Femenino , Humanos , Masculino , Neoplasias Primarias Secundarias/etiología , Estudios Retrospectivos , Factores de Riesgo , Programa de VERF , Estados Unidos
18.
J Pediatr Genet ; 6(2): 61-76, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28496993

RESUMEN

A pilot program was initiated using whole genome sequencing (WGS) to diagnose suspected genetic disorders in the Genetics Clinic at Children's Hospital of Wisconsin. Twenty-two patients underwent WGS between 2010 and 2013. Initially, we obtained a 14% (3/22) diagnosis rate over 2 years; with subsequent reanalysis, this increased to 36% (8/22). Disease causing variants were identified in SKIV2L, CECR1, DGKE, PYCR2, RYR1, PDGFRB, EFTUD2, and BCS1L. In 75% (6/8) of diagnosed cases, the diagnosis affected treatment and/or medical surveillance. Additionally, one case demonstrated a homozygous A18V variant in VLDLR that appears to be associated with a previously undescribed phenotype.

19.
Expert Rev Neurother ; 17(7): 725-736, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28548892

RESUMEN

INTRODUCTION: Immune-related neurologic toxicities are uncommon but serious adverse events that may be associated with the use of immune checkpoint inhibitors. The objective of this review is to assess the incidence and risk of neurologic toxicities which are potentially immune-related and occur with immune checkpoint treatment of solid tumors. Areas covered: PubMed database has been searched till January 2017. Clinical trials, case series and case reports reporting the occurrence of immune-related neurologic toxicities in solid tumor patients treated with immune checkpoint inhibitors were included. Eighteen trials with 4469 participants were included. The most common neurologic toxicities reported with these agents included sensory and motor peripheral neuropathies. Moreover, 17 case reports describing immune-related neurological events occurring with 22 patients were included. Expert commentary: Immune-related neurological toxicities occur uncommonly in cancer patients treated immune checkpoint inhibitors. Further studies are needed to better describe the course of these events (i.e. time to onset, time to resolution and responsiveness to different immunosuppressives).


Asunto(s)
Antineoplásicos Inmunológicos/toxicidad , Neoplasias/tratamiento farmacológico , Enfermedades del Sistema Nervioso/inducido químicamente , Enfermedades del Sistema Nervioso/inmunología , Humanos
20.
J Geriatr Oncol ; 8(4): 277-283, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28389117

RESUMEN

BACKGROUND: Scarce evidence exists regarding the management of elderly patients (≥70years) with hepatocellular carcinoma (HCC). This study assessed the presentation and outcomes of elderly patients with early stage HCC. METHODS: Patient with early stage HCC (T1/T2N0M0), ≥70years, diagnosed between 2004 and 2013 were identified from the SEER (Surveillance, Epidemiology, and End Results) database. Propensity score matching (for receipt of localized treatment) was performed considering baseline characteristics (age, gender, race, tumor (T) stage, tumor size, fibrosis score, alpha fetoprotein level and histological subtype). RESULTS: A total of 6693 patients were identified. The median age group was 75-80years, and 2457 patients received local treatment (either surgical or non-surgical treatment). Both before and after propensity score matching, cancer-specific and overall survival (P<0.0001 for all) were better in the local treatment group. When stratifying the overall survival according to age group (70-80years vs. >80years) in the post matching cohort, patients treated with local treatment have better overall survival than those not treated regardless of the age group (P<0.0001 for both groups). In multivariate analysis of the matched population: local treatment, normal AFP and age (70-80years) were associated with better overall survival (P<0.0001, P<0.0001, P=0.047; respectively). CONCLUSION: Within the known limitations of the current SEER analysis, it may be cautiously suggested that elderly patients with early HCC should be properly selected for potentially curative local therapies. Prospective confirmation of these results should be conducted.


Asunto(s)
Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/mortalidad , Estudios de Cohortes , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Masculino , Estadificación de Neoplasias , Puntaje de Propensión , Programa de VERF , Resultado del Tratamiento , Estados Unidos/epidemiología
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