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Journal of Medicine and Life Feb 2022Many aspects make irritable bowel syndrome (IBS) challenging for both patients and physicians. The unclear pathogenesis with many pathways to be explored, bothering... (Review)
Review
Many aspects make irritable bowel syndrome (IBS) challenging for both patients and physicians. The unclear pathogenesis with many pathways to be explored, bothering symptoms that affect the quality of life, and many subtypes of the condition are only a few reasons that make IBS difficult to control and obtain satisfactory results. Treatment options start with general advice for lifestyle, continue with non-pharmaceutical treatments, and finally touch classic treatments. In this review, pharmaceutical treatment options are not accounted for. Consensus groups and meta-analyses have concluded guidelines that overall are the same, with variations in the strength of recommendations and some cultural and geographical particularities. Dietary interventions, probiotics, and fibers can be seen as non-pharmaceutical treatments that coexist in various protocols because of the relevant evidence regarding their efficacy in treating IBS symptoms.
Topics: Diet; Disaccharides; Fermentation; Humans; Irritable Bowel Syndrome; Monosaccharides; Probiotics; Quality of Life
PubMed: 35419092
DOI: 10.25122/jml-2022-0028 -
Current Problems in Cancer Feb 2022Chimeric antigen receptor-modified (CAR) T-cell therapy targeting CD19 has revolutionized the treatment of relapsed or refractory B-cell lymphomas. Based on... (Review)
Review
Chimeric antigen receptor-modified (CAR) T-cell therapy targeting CD19 has revolutionized the treatment of relapsed or refractory B-cell lymphomas. Based on unprecedented response rates and durability of response in high risk B-cell lymphoma patients, anti-CD19 CAR T-cell therapy was rapidly approved by the FDA for a variety of lymphoma subtypes. Anti-CD19 CAR T-cell therapy is now considered standard of care for patients with relapsed or refractory (R/R) aggressive non-Hodgkin's Lymphoma (NHL) after 2 or more lines of therapy. Three second-generation anti-CD19 CAR T-cell products have been FDA approved for R/R aggressive B-cell lymphoma and FDA approval has been obtained for Mantle Cell Lymphoma and Follicular lymphoma as well. This has ensured broad access to CAR T-cell therapy for patients with NHL and new real-world trials have helped confirm feasibility of CAR T-cell therapy for a broad patient population. The emergence of CAR T-cell therapy will likely provide a new patient population who is status post anti-CD19 CAR T-cell therapy. Investigation of mechanisms of failure of CAR T-cell therapy and clinical trials to study strategies to address this are thus required. Here we provide a thorough review on the use of the FDA approved anti-CD19 CAR T-cell products axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel in patients with indolent or aggressive B-cell lymphoma, and touch on mechanisms of failure of CAR T-cell therapy and potential approaches which are currently under investigation to address this.
Topics: Adult; Antigens, CD19; Humans; Immunotherapy, Adoptive; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Neoplasm Recurrence, Local
PubMed: 35012754
DOI: 10.1016/j.currproblcancer.2021.100826 -
International Journal of Molecular... Mar 2021Tryptophan is an essential amino acid critical for protein synthesis in humans that has emerged as a key player in the microbiota-gut-brain axis. It is the only... (Review)
Review
Tryptophan is an essential amino acid critical for protein synthesis in humans that has emerged as a key player in the microbiota-gut-brain axis. It is the only precursor for the neurotransmitter serotonin, which is vital for the processing of emotional regulation, hunger, sleep, and pain, as well as colonic motility and secretory activity in the gut. Tryptophan catabolites from the kynurenine degradation pathway also modulate neural activity and are active in the systemic inflammatory cascade. Additionally, tryptophan and its metabolites support the development of the central and enteric nervous systems. Accordingly, dysregulation of tryptophan metabolites plays a central role in the pathogenesis of many neurologic and psychiatric disorders. Gut microbes influence tryptophan metabolism directly and indirectly, with corresponding changes in behavior and cognition. The gut microbiome has thus garnered much attention as a therapeutic target for both neurologic and psychiatric disorders where tryptophan and its metabolites play a prominent role. In this review, we will touch upon some of these features and their involvement in health and disease.
Topics: Brain; Colon; Enteric Nervous System; Gastrointestinal Microbiome; Homeostasis; Humans; Hunger; Kynurenine; Pain; Serotonin; Sleep; Tryptophan
PubMed: 33804088
DOI: 10.3390/ijms22062973 -
Current Neuropharmacology 2020The trigeminal nerve is the largest of all cranial nerves. It has three branches that provide the main sensory innervation of the anterior two-thirds of the head and... (Review)
Review
The trigeminal nerve is the largest of all cranial nerves. It has three branches that provide the main sensory innervation of the anterior two-thirds of the head and face. Trigeminal neuralgia (TN) is characterized by sudden, severe, brief, and stabbing recurrent episodes of facial pain in one or more branches of the trigeminal nerve. Pain attacks can occur spontaneously or can be triggered by non-noxious stimuli, such as talking, eating, washing the face, brushing teeth, shaving, a light touch or even a cool breeze. In addition to pain attacks, a proportion of the patients also experience persistent background pain, which along with autonomic signs and prolonged disease duration, represent predictors of worse treatment outcomes. It is now widely accepted that the presence of a neurovascular compression at the trigeminal root entry zone is an anatomic abnormality with a high correlation with classical TN. However, TN may be related to other etiologies, thus presenting different and/or additional features. Since the 1960s, the anticonvulsant carbamazepine is the drug of choice for TN treatment. Although anti-epileptic drugs are commonly used to treat neuropathic pain in general, the efficacy of carbamazepine has been largely limited to TN. Carbamazepine, however, is associated with dose-limiting side-effects, particularly with prolonged usage. Thus, a better understanding and new treatment options are urgently warranted for this rare, but excruciating disease.
Topics: Carbamazepine; Humans; Neuralgia; Trigeminal Nerve; Trigeminal Neuralgia
PubMed: 31608834
DOI: 10.2174/1570159X17666191010094350 -
Biomedicine & Pharmacotherapy =... Mar 2022When peripheral neuropathy occurs due to chemotherapy treatment, it is referred to as chemotherapy-induced peripheral neuropathy (CIPN). Typically, symptoms are sensory... (Review)
Review
When peripheral neuropathy occurs due to chemotherapy treatment, it is referred to as chemotherapy-induced peripheral neuropathy (CIPN). Typically, symptoms are sensory rather than motor and include reduced feeling and heightened sensitivity to pressure, pain, temperature, and touch. The pathophysiology of CIPN is very complex, and it involves multiple mechanisms leading to its development which will be described specifically for each chemotherapeutic class. There are currently no approved or effective agents for CIPN prevention, and Duloxetine is the only medication that is an effective treatment against CIPN. There is an unavoidable necessity to develop preventative and treatment approaches for CIPN due to its detrimental impact on patients' lives. The purpose of this review is to examine CIPN, innovative pharmacological and nonpharmacological therapy and preventive strategies for this illness, and future perspectives for this condition and its therapies.
Topics: Analgesics; Antineoplastic Agents; Antioxidants; Complementary Therapies; Humans; Neuroprotective Agents; Patient Acuity; Peripheral Nervous System Diseases; Risk Factors; Serotonin and Noradrenaline Reuptake Inhibitors; Voltage-Gated Sodium Channel Blockers
PubMed: 35104697
DOI: 10.1016/j.biopha.2022.112671 -
Nature Nov 2020The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain. Projection neurons...
The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain. Projection neurons of the anterolateral pathway are attractive therapeutic targets for pain treatment because nociceptive signals emanating from the periphery are channelled through these spinal projection neurons en route to the brain. However, the organizational logic of the anterolateral pathway remains poorly understood. Here we show that two populations of projection neurons that express the structurally related G-protein-coupled receptors (GPCRs) TACR1 and GPR83 form parallel ascending circuit modules that cooperate to convey thermal, tactile and noxious cutaneous signals from the spinal cord to the lateral parabrachial nucleus of the pons. Within this nucleus, axons of spinoparabrachial (SPB) neurons that express Tacr1 or Gpr83 innervate distinct sets of subnuclei, and strong optogenetic stimulation of the axon terminals induces distinct escape behaviours and autonomic responses. Moreover, SPB neurons that express Gpr83 are highly sensitive to cutaneous mechanical stimuli and receive strong synaptic inputs from both high- and low-threshold primary mechanosensory neurons. Notably, the valence associated with activation of SPB neurons that express Gpr83 can be either positive or negative, depending on stimulus intensity. These findings reveal anatomically, physiologically and functionally distinct subdivisions of the SPB tract that underlie affective aspects of touch and pain.
Topics: Animals; Axons; Female; Male; Mechanotransduction, Cellular; Mice; Neural Pathways; Pain; Philosophy; Receptors, G-Protein-Coupled; Sensory Receptor Cells; Skin; Spinal Cord; Synapses; Touch
PubMed: 33116307
DOI: 10.1038/s41586-020-2860-1 -
BMJ (Clinical Research Ed.) Mar 2021To describe the comparative efficacy of drug and non-drug interventions for reducing symptoms of depression in people with dementia who experience depression as a... (Comparative Study)
Comparative Study Meta-Analysis
OBJECTIVE
To describe the comparative efficacy of drug and non-drug interventions for reducing symptoms of depression in people with dementia who experience depression as a neuropsychiatric symptom of dementia or have a diagnosis of a major depressive disorder.
DESIGN
Systematic review and meta-analysis.
DATA SOURCES
Medline, Embase, the Cochrane Library, CINAHL, PsycINFO, and grey literature between inception and 15 October 2020.
ELIGIBILITY CRITERIA FOR STUDY SELECTION
Randomised trials comparing drug or non-drug interventions with usual care or any other intervention targeting symptoms of depression in people with dementia.
MAIN OUTCOME MEASURES
Pairs of reviewers screened studies, abstracted aggregate level data, and appraised risk of bias with the Cochrane risk of bias tool, which facilitated the derivation of standardised mean differences and back transformed mean differences (on the Cornell scale for depression in dementia) from bayesian random effects network meta-analyses and pairwise meta-analyses.
RESULTS
Of 22 138 citations screened, 256 studies (28 483 people with dementia) were included. Missing data posed the greatest risk to review findings. In the network meta-analysis of studies including people with dementia without a diagnosis of a major depressive disorder who were experiencing symptoms of depression (213 studies; 25 177 people with dementia; between study variance 0.23), seven interventions were associated with a greater reduction in symptoms of depression compared with usual care: cognitive stimulation (mean difference -2.93, 95% credible interval -4.35 to -1.52), cognitive stimulation combined with a cholinesterase inhibitor (-11.39, -18.38 to -3.93), massage and touch therapy (-9.03, -12.28 to -5.88), multidisciplinary care (-1.98, -3.80 to -0.16), occupational therapy (-2.59, -4.70 to -0.40), exercise combined with social interaction and cognitive stimulation (-12.37, -19.01 to -5.36), and reminiscence therapy (-2.30, -3.68 to -0.93). Except for massage and touch therapy, cognitive stimulation combined with a cholinesterase inhibitor, and cognitive stimulation combined with exercise and social interaction, which were more efficacious than some drug interventions, no statistically significant difference was found in the comparative efficacy of drug and non-drug interventions for reducing symptoms of depression in people with dementia without a diagnosis of a major depressive disorder. Clinical and methodological heterogeneity precluded network meta-analysis of studies comparing the efficacy of interventions specifically for reducing symptoms of depression in people with dementia and a major depressive disorder (22 studies; 1829 patients).
CONCLUSIONS
In this systematic review, non-drug interventions were found to be more efficacious than drug interventions for reducing symptoms of depression in people with dementia without a major depressive disorder.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42017050130.
Topics: Antidepressive Agents; Cognitive Behavioral Therapy; Combined Modality Therapy; Dementia; Depression; Exercise Therapy; Humans; Network Meta-Analysis; Social Support; Therapy, Soft Tissue
PubMed: 33762262
DOI: 10.1136/bmj.n532 -
American Journal of Physiology. Cell... Mar 2023PIEZO1 and PIEZO2 are mechanosensitive cation channels that are highly expressed in numerous tissues throughout the body and exhibit diverse, cell-specific functions in... (Review)
Review
PIEZO1 and PIEZO2 are mechanosensitive cation channels that are highly expressed in numerous tissues throughout the body and exhibit diverse, cell-specific functions in multiple organ systems. Within the musculoskeletal system, PIEZO1 functions to maintain muscle and bone mass, sense tendon stretch, and regulate senescence and apoptosis in response to mechanical stimuli within cartilage and the intervertebral disc. PIEZO2 is essential for transducing pain and touch sensations as well as proprioception in the nervous system, which can affect musculoskeletal health. PIEZO1 and PIEZO2 have been shown to act both independently as well as synergistically in different cell types. Conditions that alter PIEZO channel mechanosensitivity, such as inflammation or genetic mutations, can have drastic effects on these functions. For this reason, therapeutic approaches for PIEZO-related disease focus on altering PIEZO1 and/or PIEZO2 activity in a controlled manner, either through inhibition with small molecules, or through dietary control and supplementation to maintain a healthy cell membrane composition. Although many opportunities to better understand PIEZO1 and PIEZO2 remain, the studies summarized in this review highlight how crucial PIEZO channels are to musculoskeletal health and point to promising possible avenues for their modulation as a therapeutic target.
Topics: Cell Membrane; Ion Channels; Mechanotransduction, Cellular; Muscles; Musculoskeletal System; Humans
PubMed: 36717101
DOI: 10.1152/ajpcell.00544.2022 -
Health Technology Assessment... Jun 2022Carers report unmet need for occupational therapy services addressing sensory difficulties in autism, yet insufficient evidence exists to recommend a therapeutic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Carers report unmet need for occupational therapy services addressing sensory difficulties in autism, yet insufficient evidence exists to recommend a therapeutic approach.
OBJECTIVES
Our aim was to determine the clinical effectiveness and cost-effectiveness of sensory integration therapy for children with autism and sensory difficulties across behavioural, functional and quality-of-life outcomes.
DESIGN
We carried out a parallel-group randomised controlled trial, incorporating an internal pilot and a process evaluation. Randomisation utilised random permuted blocks.
SETTING AND PARTICIPANTS
Children were recruited via services and self-referral in Wales and England. Inclusion criteria were having an autism diagnosis, being in mainstream primary education and having definite/probable sensory processing difficulties. Exclusion criteria were having current/previous sensory integration therapy and current applied behaviour analysis therapy.
INTERVENTION
The intervention was manualised sensory integration therapy delivered over 26 weeks and the comparator was usual care.
OUTCOMES
The primary outcome was problem behaviours (determined using the Aberrant Behavior Checklist), including irritability/agitation, at 6 months. Secondary outcomes were adaptive behaviour, functioning and socialisation (using the Vineland Adaptive Behavior Scales); carer stress (measured using the Autism Parenting Stress Index); quality of life (measured using the EuroQol-5 Dimensions and Carer Quality of Life); functional change (according to the Canadian Occupational Performance Measure); sensory processing (determined using the Sensory Processing Measure™ at screening and at 6 months to examine mediation effects); and cost-effectiveness (assessed using the Client Service Receipt Inventory). Every effort was made to ensure that outcome assessors were blind to allocation.
RESULTS
A total of 138 participants were randomised ( = 69 per group). Usual care was significantly different from the intervention, which was delivered with good fidelity and adherence and minimal contamination, and was associated with no adverse effects. Trial procedures and outcome measures were acceptable. Carers and therapists reported improvement in daily functioning. The primary analysis included 106 participants. There were no significant main effects of the intervention at 6 or 12 months. The adjusted mean difference between groups on the Aberrant Behavior Checklist - irritability at 6 months post randomisation was 0.40 (95% confidence interval -2.33 to 3.14; = 0.77). Subgroup differences in irritability/agitation at 6 months were observed for sex of child (intervention × female = 6.42, 95% confidence interval 0.00 to 12.85; = 0.050) and attention deficit hyperactivity disorder (intervention × attention deficit hyperactivity disorder = -6.77, 95% confidence interval -13.55 to -0.01; = 0.050). There was an effect on carer stress at 6 months by region (intervention × South England = 7.01, 95% confidence interval 0.45 to 13.56; = 0.04) and other neurodevelopmental/genetic conditions (intervention × neurodevelopmental/genetic condition = -9.53, 95% confidence interval -18.08 to -0.98; = 0.030). Carer-rated goal performance and satisfaction increased across sessions ( < 0.001), with a mean change of 2.75 (95% confidence interval 2.14 to 3.37) for performance and a mean change of 3.34 (95% confidence interval 2.63 to 4.40) for satisfaction. Health economic evaluation suggests that sensory integration therapy is not cost-effective compared with usual care alone.
LIMITATIONS
Limitations included variability of the intervention setting (i.e. NHS vs. private), delay for some receiving therapy, an error in administration of Vineland Adaptive Behavior Scales and no measurement of comparator arm goal performance.
CONCLUSIONS
The intervention did not demonstrate clinical benefit above standard care. Subgroup effects are hypothesis-generating only. The intervention is likely to be effective for individualised performance goals, although it is unclear whether effects were in addition to standard care or were maintained.
FUTURE WORK
Further investigation of subgroup effects is needed.
TRIAL REGISTRATION
This trial is registered as ISRCTN14716440.
FUNDING
This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 26, No. 29. See the NIHR Journals Library website for further project information.
Topics: Autistic Disorder; Canada; Child; Female; Humans; Perception; Quality of Life; Treatment Outcome
PubMed: 35766242
DOI: 10.3310/TQGE0020 -
JAMA Oncology Dec 2021Metastatic non-small cell lung cancer (mNSCLC) with EGFR exon 20 insertion (EGFRex20ins) mutations is associated with a poor prognosis. Mobocertinib is an oral tyrosine... (Clinical Trial)
Clinical Trial
Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial.
IMPORTANCE
Metastatic non-small cell lung cancer (mNSCLC) with EGFR exon 20 insertion (EGFRex20ins) mutations is associated with a poor prognosis. Mobocertinib is an oral tyrosine kinase inhibitor designed to selectively target EGFRex20ins mutations.
OBJECTIVE
To evaluate treatment outcomes and safety of mobocertinib in patients with previously treated EGFRex20ins-positive mNSCLC.
DESIGN, SETTING, AND PARTICIPANTS
This 3-part, open-label, phase 1/2 nonrandomized clinical trial with dose-escalation/dose-expansion cohorts (28 sites in the US) and a single-arm extension cohort (EXCLAIM; 40 sites in Asia, Europe, and North America) was conducted between June 2016 and November 2020 (data cutoff date). The primary analysis populations were the platinum-pretreated patients (PPP) cohort and the EXCLAIM cohort. The PPP cohort included 114 patients with platinum-pretreated EGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily from the dose-escalation (n = 6), dose-expansion (n = 22), and EXCLAIM (n = 86) cohorts. The EXCLAIM cohort included 96 patients with previously treated EGFRex20ins-positive mNSCLC (10 were not platinum pretreated and thus were excluded from the PPP cohort).
INTERVENTIONS
Mobocertinib 160 mg once daily.
MAIN OUTCOMES AND MEASURES
The primary end point of the PPP and EXCLAIM cohorts was confirmed objective response rate (ORR) assessed by independent review committee (IRC). Secondary end points included confirmed ORR by investigator, duration of response, progression-free survival, overall survival, and safety.
RESULTS
Among the PPP (n = 114) and EXCLAIM (n = 96) cohorts, the median (range) age was 60 (27-84) and 59 (27-80) years, respectively; most patients were women (75 [66%] and 62 [65%], respectively) and of Asian race (68 [60%] and 66 [69%], respectively). At data cutoff, median follow-up was 14.2 months in the PPP cohort (median 2 prior anticancer regimens; 40 [35%] had baseline brain metastases), with confirmed ORR of 28% (95% CI, 20%-37%) by IRC assessment and 35% (95% CI, 26%-45%) by investigator assessment; median duration of response by IRC assessment was 17.5 months (95% CI, 7.4-20.3). Median progression-free survival by IRC assessment was 7.3 months (95% CI, 5.5-9.2). Median overall survival was 24.0 months (95% CI, 14.6-28.8). In the EXCLAIM cohort, median follow-up was 13.0 months, with confirmed ORR by IRC assessment of 25% (95% CI, 17%-35%) and by investigator assessment of 32% (95% CI, 23%-43%). The most common treatment-related adverse events were diarrhea and rash.
CONCLUSIONS AND RELEVANCE
In this open-label, phase 1/2 nonrandomized clinical trial, mobocertinib was associated with clinically meaningful benefit in patients with previously treated EGFRex20ins-positive mNSCLC, with a manageable safety profile.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02716116.
Topics: Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Exons; Female; Humans; Indoles; Lung Neoplasms; Platinum; Protein Kinase Inhibitors; Pyrimidines; Treatment Outcome
PubMed: 34647988
DOI: 10.1001/jamaoncol.2021.4761