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The New England Journal of Medicine Apr 2020No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1.
BACKGROUND
No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1.
METHODS
We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable).
RESULTS
A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia.
CONCLUSIONS
In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).
Topics: Adolescent; Benzimidazoles; Child; Child, Preschool; Female; Humans; Male; Mitogen-Activated Protein Kinase Kinases; Nausea; Neurofibroma, Plexiform; Neurofibromatosis 1; Pain; Patient Reported Outcome Measures; Progression-Free Survival; Protein Kinase Inhibitors; Tumor Burden
PubMed: 32187457
DOI: 10.1056/NEJMoa1912735 -
Osteoarthritis and Cartilage Apr 2022To systematically review the literature on the relationship between markers of inflammation and pain in patients with knee osteoarthritis (OA). (Review)
Review
OBJECTIVE
To systematically review the literature on the relationship between markers of inflammation and pain in patients with knee osteoarthritis (OA).
METHODS
We searched MEDLINE, Web of Science and EMBASE databases from inception until June 2021. Eligible articles had to report on the association between inflammation (as measured by effusion, synovitis, baker's cysts, cytokines and C-reactive protein) and pain in patients with radiographic knee OA. Two reviewers independently performed a screening on title and abstracts, data extraction and risk of bias assessment using the Newcastle-Ottawa Scale (NOS). A best evidence synthesis was conducted for each inflammatory sign included in this review.
RESULTS
37 studies were included. Articles reported on the following measures: effusion or synovitis assessed via ultrasound (n = 9) or magnetic resonance imaging (MRI) (n = 17); baker's cyst (n = 3); cytokine concentrations (n = 11); and C-reactive protein levels (n = 4). The strength of the association between inflammation and pain does not exceed the moderate level (i.e., correlation coefficient values ranging from 0.19 to 0.61). Moderate levels of evidence were found for the association between synovitis (measured with ultrasound or contrast enhanced MRI) and pain. The levels of evidence between effusion (assessed via ultrasound), effusion/synovitis (assessed via non-contrast enhanced MRI), Baker's cyst, cytokines, C-reactive protein and pain were conflicting.
CONCLUSIONS
Different inflammatory markers are associated with pain but the correlation ranges from weak to moderate, and the quality of evidence from conflicting to moderate. Further research is needed to strengthen the level of evidence and to establish mechanisms.
Topics: C-Reactive Protein; Cytokines; Humans; Inflammation; Knee Joint; Magnetic Resonance Imaging; Osteoarthritis, Knee; Pain; Popliteal Cyst; Synovitis
PubMed: 34968719
DOI: 10.1016/j.joca.2021.12.003 -
HPB : the Official Journal of the... Jan 2023Choledochal cysts (CCs) are rare cystic dilatations of the intrahepatic and/or extrahepatic bile ducts. We review the pathophysiology, diagnosis, and management of CCs. (Review)
Review
BACKGROUND
Choledochal cysts (CCs) are rare cystic dilatations of the intrahepatic and/or extrahepatic bile ducts. We review the pathophysiology, diagnosis, and management of CCs.
METHODS
MEDLINE/PubMed and Web of Science databases were queried for "choledochal cyst", "bile duct cyst", "choledochocele", and "Caroli disease". Data were synthesized and systematically reviewed.
RESULTS
Classified according to the Todani Classification, CCs are generally believed to arise secondary to reflux of pancreatic enzymes into the biliary tree due to anomalous pancreaticobiliary duct union. Complications of CCs include abdominal pain, jaundice, cystolithiasis, cholecystitis, pancreatitis, liver abscess, liver cirrhosis and malignant transformation (3-7.5%). Radiological and endoscopic imaging is the cornerstone of CC diagnosis and full delineation of cyst anatomy is imperative for proper management. Management is generally guided by cyst classification with complete cyst excision necessary for CCs with high potential of malignant transformation such as types I and IV. 5-year overall survival after choledochal cyst excision is 95.5%.
CONCLUSION
Most CCs should undergo surgical intervention to mitigate the risk of cyst related complications such as cholangitis and malignant transformation.
Topics: Humans; Choledochal Cyst; Pancreatitis; Diagnostic Imaging; Common Bile Duct; Liver Cirrhosis
PubMed: 36257874
DOI: 10.1016/j.hpb.2022.09.010 -
Deutsches Arzteblatt International May 2020Neurofibromatosis of types 1 and 2 (NF1, NF2) and schwannomatosis are the diseases that make up the neurofibromatosis spectrum. With respective incidences of 1 in 3000,... (Review)
Review
BACKGROUND
Neurofibromatosis of types 1 and 2 (NF1, NF2) and schwannomatosis are the diseases that make up the neurofibromatosis spectrum. With respective incidences of 1 in 3000, 1 in 33 000, and 1 in 60 000 births, they form part of the group of rare tumor-suppressor syndromes. They give rise to a greater tumor burden for the nervous system than any other type of neoplastic disease. New approaches to symptomatic treatment are emerging.
METHODS
This review is based on articles retrieved by a selective literature search on the pathogenesis, diagnosis, and treatment of the neurofibromatoses.
RESULTS
NF1 and NF2 are monogenic diseases, while the genetics of schwannomatosis is complex. The three entities are clinically and pathophysiologically distinct. An important aspect of their tumor biology is the alternation of growth phases and growth pauses. Correlations between genotypes and phenotypes are variable, while new mutations and genetic mosaics are common. Ninety-nine percent of patients with NF1 have six or more café-au-lait spots by the age of 12 months; 90-95% of patients with NF2 develop bilateral vestibular schwannomas. In schwannomatosis, pain is the most prominent symptom; two-thirds of those affected develop spinal schwannomas. The severity and prognosis of these disorders are not closely correlated with the radiological findings; rather, neurologic deficits, malignant transformation, and psychosocial stress are of greater clinical importance. Advances in knowledge of pathophysiology have led to the development of targeted treatment approaches. Examples include the off-label treatment of vestibular schwannomas with bevacizumab and of plexiform neurofibromas with MEK inhibitors.
CONCLUSION
Patients with neurofibromatoses need individualized care. They should be treated in centers of expertise where interdisciplinary consultation is available and new types of pharmacotherapy can be provided.
Topics: Humans; Neurofibromatoses
PubMed: 32657748
DOI: 10.3238/arztebl.2020.0354 -
Neuro-oncology Nov 2022The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated... (Review)
Review
The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low-grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.
Topics: Child; Humans; Consensus; Mitogen-Activated Protein Kinase Kinases; Neurofibroma, Plexiform; Neurofibromatosis 1; Protein Kinase Inhibitors
PubMed: 35788692
DOI: 10.1093/neuonc/noac165 -
Nature Cell Biology Aug 2022Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus. It affects many women during their reproductive age, causing years of pelvic...
Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus. It affects many women during their reproductive age, causing years of pelvic pain and potential infertility. Its pathophysiology remains largely unknown, which limits early diagnosis and treatment. We characterized peritoneal and ovarian lesions at single-cell transcriptome resolution and compared them to matched eutopic endometrium, unaffected endometrium and organoids derived from these tissues, generating data on over 122,000 cells across 14 individuals. We spatially localized many of the cell types using imaging mass cytometry. We identify a perivascular mural cell specific to the peritoneal lesions, with dual roles in angiogenesis promotion and immune cell trafficking. We define an immunotolerant peritoneal niche, fundamental differences in eutopic endometrium and between lesion microenvironments and an unreported progenitor-like epithelial cell subpopulation. Altogether, this study provides a holistic view of the endometriosis microenvironment that represents a comprehensive cell atlas of the disease in individuals undergoing hormonal treatment, providing essential information for future therapeutics and diagnostics.
Topics: Choristoma; Endometriosis; Endometrium; Female; Humans; Ovarian Cysts; Ovarian Neoplasms; Single-Cell Analysis; Tumor Microenvironment
PubMed: 35864314
DOI: 10.1038/s41556-022-00961-5 -
Neuro-oncology Oct 2023Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our...
BACKGROUND
Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies.
METHODS
This manuscript includes data from the phase 1 and phase 2, stratum 1 study which included participants with clinically significant PN-related morbidity. Participants received continuous selumetinib dosing (1 cycle = 28 days). Safety and efficacy data through February 27, 2021 are included. PN response assessed by volumetric magnetic resonance imaging analysis: Confirmed partial response (cPR) ≥20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants completed patient-reported outcome measures assessing tumor pain intensity (Numeric Rating Scale-11) and interference of pain in daily life (pain interference index).
RESULTS
For the 74 children (median age 10.3 years; range 3-18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment was 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) lasting ≥ 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain interference (n = 18, P = .0059) showed durable improvement from baseline to 48 cycles. No new safety signals were identified; however, some developed known selumetinib-related adverse events (AEs) for the first time after several years of treatment.
CONCLUSIONS
With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain beyond that previously reported at 1 year. No new safety signals were identified; however, ongoing monitoring for known selumetinib-related AEs is needed while treatment continues.
Topics: Child; Humans; Neurofibromatosis 1; Neurofibroma, Plexiform; Benzimidazoles; Pain
PubMed: 37115514
DOI: 10.1093/neuonc/noad086 -
Journal of Nippon Medical School =... Mar 2022Simple hepatic cysts are typically saccular, thin-walled masses with fluid-filled epithelial lined cavities. They arise from aberrant bile duct cells that develop during...
Simple hepatic cysts are typically saccular, thin-walled masses with fluid-filled epithelial lined cavities. They arise from aberrant bile duct cells that develop during embryonic development. With the development of diagnostic modalities such as ultrasonography (US), CT, and MRI, simple hepatic cysts are frequently detected in clinical examinations. US is the most useful and noninvasive tool for diagnosis of simple hepatic cysts and can usually differentiate simple hepatic cysts from abscesses, hemangiomas, and malignancies. Cysts with irregular walls, septations, calcifications, or daughter cysts on US should be evaluated with enhanced CT or MRI, to differentiate simple hepatic cysts from cystic neoplasms or hydatid cysts. Growth and compression of hepatic cysts cause abdominal discomfort, pain, distension, and dietary symptoms such as nausea, vomiting, a feeling of fullness, and early satiety. Complications of simple hepatic cysts include infection, spontaneous hemorrhage, rupture, and external compression of biliary tree or major vessels. Asymptomatic simple hepatic cysts do not require treatment. Treatment for symptomatic simple hepatic cysts includes percutaneous aspiration, aspiration followed by sclerotherapy, and surgery. The American College of Gastroenterology clinical guidelines recommend laparoscopic fenestration because of its high success rate and low invasiveness. Percutaneous procedures for treatment of simple hepatic cysts are particularly effective for immediate palliation of patient symptoms; however, they are not generally recommended because of the high rate of recurrence. Management of simple hepatic cysts requires correct differentiation from neoplasms and infections, and selection of a reliable treatment.
Topics: Cysts; Humans; Liver Diseases; Magnetic Resonance Imaging; Ultrasonography
PubMed: 34526451
DOI: 10.1272/jnms.JNMS.2022_89-115 -
Nature Medicine Jan 2021Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of...
Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.
Topics: Adolescent; Adult; Anilides; Animals; Disease Models, Animal; Female; Genes, Neurofibromatosis 1; Humans; Male; Mice; Mice, Mutant Strains; Neurofibroma, Plexiform; Neurofibromatosis 1; Pain Measurement; Prospective Studies; Protein Kinase Inhibitors; Pyridines; Quality of Life; Receptor Protein-Tyrosine Kinases; Translational Research, Biomedical; Young Adult
PubMed: 33442015
DOI: 10.1038/s41591-020-01193-6 -
Journal of Internal Medicine Mar 2023Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with... (Review)
Review
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH) D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH) D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.
Topics: Humans; Phosphates; Hypophosphatemia; Paraneoplastic Syndromes; Fractures, Bone; Pain; Fibroblast Growth Factors
PubMed: 36511653
DOI: 10.1111/joim.13593