The Role of Nucleophosmin 1 (NPM1) Mutation in the Diagnosis and Management of Myeloid Neoplasms

Nucleophosmin (NPM1) is a multifunctional protein with both proliferative and growth-suppressive roles in the cell. In humans, NPM1 is involved in tumorigenesis via chromosomal translocations, deletions, or mutation. Acute myeloid leukemia (AML) with mutated NPM1, a distinct diagnostic entity by the current WHO Classification of myeloid neoplasm, represents the most common diagnostic subtype in AML and is associated with a favorable prognosis. The persistence of NPM1 mutation in AML at relapse makes this mutation an ideal target for minimal measurable disease (MRD) detection. The clinical implication of this is far-reaching because NPM1-mutated AML is currently classified as being of standard risk, with the best treatment strategy (transplantation versus chemotherapy) yet undefined. Myeloid neoplasms with NPM1 mutations and <20% blasts are characterized by an aggressive clinical course and a rapid progression to AML. The pathological classification of these cases remains controversial. Future studies will determine whether NPM1 gene mutation may be sufficient for diagnosing NPM1-mutated AML independent of the blast count. This review aims to summarize the role of NPM1 in normal cells and in human cancer and discusses its current role in clinical management of AML and related myeloid neoplasms.

Collapsing Focal Segmental Glomerulosclerosis in Viral Infections

Collapsing glomerulopathy represents a special variant of the proteinuric kidney disease focal segmental glomerulosclerosis (FSGS). Histologically, the collapsing form of FSGS (cFSGS) is characterized by segmental or global condensation and obliteration of glomerular capillaries, the appearance of hyperplastic and hypertrophic podocytes and severe tubulointerstitial damage. Clinically, cFSGS patients present with acute kidney injury, nephrotic-range proteinuria and are at a high risk of rapid progression to irreversible kidney failure. cFSGS can be attributed to numerous etiologies, namely, viral infections like HIV, cytomegalovirus, Epstein–Barr-Virus, and parvovirus B19 and also drugs and severe ischemia. Risk variants of the APOL1 gene, predominantly found in people of African descent, increase the risk of developing cFSGS. Patients infected with the new Corona-Virus SARS-CoV-2 display an increased rate of acute kidney injury (AKI) in severe cases of COVID-19. Besides hemodynamic instability, cytokine mediated injury and direct viral entry and infection of renal epithelial cells contributing to AKI, there are emerging reports of cFSGS associated with SARS-CoV-2 infection in patients of mainly African ethnicity. The pathogenesis of cFSGS is proposed to be linked with direct viral infection of podocytes, as described for HIV-associated glomerulopathy. Nevertheless, there is growing evidence that the systemic inflammatory cascade, activated in acute viral infections like COVID-19, is a major contributor to the impairment of basic cellular functions in podocytes. This mini review will summarize the current knowledge on cFSGS associated with viral infections with a special focus on the influence of systemic immune responses and potential mechanisms propagating the development of cFSGS.

Pediatric spinal cord diffuse midline glioma, H3 K27-altered with intracranial and spinal leptomeningeal spread: A case report

Primary spinal cord high-grade gliomas, including those histologically identified as glioblastoma (GBM), are a rare entity in the pediatric population but should be considered in the differential diagnosis of intramedullary lesions. Pediatric spinal cord high-grade gliomas have an aggressive course with poor prognosis. The aim of this case report is to present a 15-year-old female adolescent with histopathologically confirmed spinal cord GBM with H3F3A K27 M mutation consistent with a diffuse midline glioma (DMG), H3 K27-altered, CNS WHO grade 4 with leptomeningeal seeding on initial presentation. As imaging features of H3 K27-altered DMGs are non-specific and may mimic more frequently encountered neoplastic diseases as well as demyelinating disorders, severe neurological deficits at presentation with short duration, rapid progression, and early leptomeningeal seeding should however raise the suspicion for a pediatric-type diffuse high-grade glioma like DMG, H3 K27-altered.

OncoSNIPE® Study Protocol, a study of molecular profiles associated with development of resistance in solid cancer patients

Background Nowadays, evaluation of the efficacy and the duration of treatment, in context of monitoring patients with solid tumors, is based on the RECIST methodology. With these criteria, resistance and/or insensitivity are defined as tumor non-response which does not allow a good understanding of the diversity of the underlying mechanisms. The main objective of the OncoSNIPE® collaborative clinical research program is to identify early and late markers of resistance to treatment. Methods Multicentric, interventional study with the primary objective to identify early and / or late markers of resistance to treatment, in 600 adult patients with locally advanced or metastatic triple negative or Luminal B breast cancer, non-small-cell lung cancer or pancreatic ductal adenocarcinoma. Patients targeted in this study have all rapid progression of their pathology, making it possible to obtain models for evaluating markers of early and / or late responses over the 2-year period of follow-up, and thus provide the information necessary to understand resistance mechanisms. To explore the phenomena of resistance, during therapeutic response and / or progression of the pathology, we will use a multidisciplinary approach including high-throughput sequencing (Exome-seq and RNAseq), clinical data, medical images and immunological profile by ELISA. Patients will have long-term follow-up with different biological samples, at baseline (blood and biopsy) and at each tumoral evaluation or tumoral progression evaluated by medical imaging. Clinical data will be collected through a dedicated Case Report Form (CRF) and enriched by semantic extraction based on the French ConSoRe (Continuum Soins Recherche) initiative, a dedicated Semantic Clinical Data Warehouse (SCDW) to cancer. The study is sponsored by Oncodesign (Dijon, France) and is currently ongoing. Discussion The great diversity of intrinsic or acquired molecular mechanisms involved in resistance to treatment constitutes a real therapeutic issue. Improving understanding of mechanisms of resistance of cancer cells to anti-tumor treatments is therefore a major challenge. The OncoSNIPE cohort will lead to a better understanding of the mechanisms of resistance and will allow to explore new mechanisms of actions and to discover new therapeutic targets or strategies making it possible to circumvent the escape in different types of cancer. Trial registration Clinicaltrial.gov. Registered 16 September 2020, https://clinicaltrials.gov/ct2/show/NCT04548960?term=oncosnipe&draw=2&rank=1 and ANSM ID RCB 2017-A02018-45.

A Matter of Time: Delayed Presentation and Rapid Progression from Gonadotropin-Independent to Gonadotropin-Dependent Precocious Puberty following Successful Treatment for a Leydig Cell Tumor

Leydig cell tumors, most often benign, are a rare cause of isosexual gonadotropin-independent precocious puberty in boys due to secretion of testosterone. Very rarely do these tumors produce estrogen, causing gynecomastia. Testicular sparing surgery is the mainstay of treatment currently although radical orchidectomy was the choice in the past. Following surgery, clinical signs improve along with a revision of biochemical changes. Occasionally, it has been reported few children are progressed to gonadotropin-dependent precocious puberty (GDPP) after initial clinical and biochemical recovery. Gonadotropin receptor analogs have been successful on them to halt the progression of puberty, and growth hormone administration has been used to optimize the adult height. Here, we report a case of a 10-year-old boy who presented very late due to failure in recognition of features of puberty due to a Leydig cell tumor. Even though he underwent successful radical orchidectomy, just within 1 month following surgery, he entered GDPP in contrast to the published cases where it was earliest detected at 3 months.

Integrative Profiling of Amyotrophic Lateral Sclerosis Lymphoblasts Identifies Unique Metabolic and Mitochondrial Disease Fingerprints

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with a rapid progression and no effective treatment. Metabolic and mitochondrial alterations in peripheral tissues of ALS patients may present diagnostic and therapeutic interest. We aimed to identify mitochondrial fingerprints in lymphoblast from ALS patients harboring SOD1 mutations (mutSOD1) or with unidentified mutations (undSOD1), compared with age/sex matched controls. Three groups of lymphoblasts, from mutSOD1 or undSOD1 ALS patients and age/sex-matched controls, were obtained from Coriell Biobank and divided into 3 age/sex-matched cohorts. Mitochondria-associated metabolic pathways were analyzed using Seahorse MitoStress and ATP Rate assays, complemented with metabolic phenotype microarrays, metabolite levels, gene expression, and protein expression and activity. Pooled (all cohorts) and paired (intra-cohort) analyses were performed by using bioinformatic tools, and the features with higher information gain values were selected and used for principal component analysis and Naïve Bayes classification. Pooled analysis revealed that undSOD1 patients had statistically higher glycolytic ATP production rate and lower Tfam protein content compared to controls, which were also the experimental features highlighted by multidimensional analysis. Metabolic phenotypic profiles in lymphoblasts from ALS patients with mutSOD1 and undSOD1 revealed unique age-dependent different substrate oxidation profiles. For most parameters, different patterns of variation were found between cohorts, which may be due to age or sex. In the present work, we investigated several metabolic and mitochondrial hallmarks in lymphoblasts from each donor and, although a high heterogeneity of results was found, we identified specific metabolic and mitochondrial fingerprints that may have a diagnostic and therapeutic interest.

Metabolic Reprogramming Underlying Brain Metastasis of Breast Cancer

The development of brain metastasis is a major cause of death in patients with breast cancer, characterized by rapid progression of the disease and poor prognosis, and lack of effective treatment has existed as an unresolved issue clinically. Extensive research has shown that a variety of metabolic changes associated with cellular metastasis exist in primary breast cancer or brain metastases, therefore to elucidate metabolic characteristics at each step of the metastasis cascade will provide important clues to the efficient treatment. In this review, we discuss the changes in metabolic patterns of breast cancer cells at every step of metastasis for exploring the potential therapeutic target based on metabolic reprogramming, and provide new insights on the design and development of drugs for breast cancer brain metastasis.

Acute worsening of native lung fibrosis after single lung transplantation for pulmonary fibrosis: two case reports

Background In patients receiving single lung transplantation for idiopathic pulmonary fibrosis, worsening of fibrosis of the native lung is usually progressive over time, with no significant effects on gas exchange. Case presentation Here, we describe the cases of two Caucasian male recipients of single lung transplants for idiopathic pulmonary fibrosis, 65 and 62 years of age, who exhibited acute worsening of lung fibrosis after an episode of serious viral infection (cytomegalovirus primo-infection in one case and COVID-19 in the other). In both cases, along with opacification of the native lung over several days, the patients presented acute respiratory failure that required the use of high-flow nasal oxygen therapy. Eventually, hypoxemic respiratory failure resolved, but with rapid progression of fibrosis of the native lung. Conclusion We conclude that acute worsening of fibrosis on the native lung secondary to a severe viral infection should be added to the list of potential complications developing on the native lung after single lung transplantation for idiopathic pulmonary fibrosis.

What Should the Earliest Age be for Clinical Trials of Corneal Crosslinking for Keratoconus?

Keratoconus is often diagnosed in the second or third decade of life, with a younger mean age at diagnosis more likely among those of Middle Eastern and Asian descent (1). Studies have shown that patients with severe forms of keratoconus present at a younger age (usually in the second decade of life), and these patients have more rapid progression of disease (2-6). Pediatric keratoconus is generally attributed to disease manifesting in those less than 18 years of age, however studies that looked at progression in different age groups used varying age criteria. Léoni-Mesplié et al. found that at diagnosis, keratoconus is often more advanced in children (defined as ?15 years) than in adults (?27 years), while Tuft et al. found that patients ?18 years at time of diagnosis progressed to transplantation faster than patients >18 years of age (5-6). McMahon et al. found that the rate of change in corneal curvature was substantially greater in patients <20 years old and slowed down dramatically in those ?20 years old (7). Until the late 1990s when corneal crosslinking (CXL) was initially developed (8) there were no effective means to halt or slow progression, and keratoplasty was the definitive treatment. There was some assertion in the literature that certain contact lenses and intracorneal rings may help slow progression, but no definitive evidence was ever presented (9-11). Ring segments have been shown to improve best corrected visual acuity as well as contact lens tolerance, but do not alter progression of disease (9, 11).