De-escalation of corticosteroids and clonal remission in UBA1 mutation-driven VEXAS syndrome with 5-azacytidine.

Not available.

Brain SPECT as an Imaging Biomarker for Evaluating Effects of Novel Treatments in Psychiatry-A Case Series.

The difficulties of evaluating patients with complex neuropsychiatric conditions and prescribing appropriate treatments are well known. Imaging complements clinical assessments and allows a clinician to narrow the differential diagnosis by facilitating accurate and efficient evaluation. This is particularly relevant to neuropsychiatric conditions that are often diagnosed using a trial-and error process of exclusion. Single Photon Emission Computed Tomography (SPECT) is a functional brain imaging procedure that allows practitioners to measure the functional changes of gray matter structures based on regional cerebral blood flow (rCBF). The accurate diagnosis and treatment selection in psychiatry is challenging due to complex cases and frequent comorbidities. However, such complex neuropsychiatric conditions are increasingly benefitting from new treatment approaches, in addition to established medications. Among these are combination transcranial magnetic stimulation with ketamine infusions (CTK), hyperbaric oxygen therapy (HBOT) and perispinal administration of etanercept (PSE). This article provides readers with six case study examples that demonstrate how brain SPECT imaging can be used, both as a diagnostic tool, and as a potential biomarker for monitoring and evaluating novel treatments for patients with complex neuropsychiatric conditions. Six patients were assessed in our clinic and baseline brain SPECT imagesTourettes and a long history of alcohol were visually compared with SPECT images collected after periods of treatment with CTK or HBOT followed by PSE. This retrospective review demonstrates the clinical utility of these novel treatments and describes how SPECT imaging can complement standard diagnostic assessments. A novel display technique for SPECT images is described and we argue that SPECT imaging can be used for monitoring biomarker for clinical change.

Impact of somatic mutations in myelodysplastic patients with isolated partial or total loss of chromosome 7.

Monosomy 7 [-7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with -7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with -7). Patients with del(7q) or -7 had similar demographic and disease-related characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in -7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0-8). There was no difference in mutation frequency between the two groups. Patients harbouring ≥2 mutations had a worse outcome than patients with <2 or no mutations (leukaemic transformation at 24 months, 38% and 20%, respectively, p = 0.044). Untreated patients with del(7q) had better overall survival (OS) compared with -7 (median OS, 34 vs 17 months, p = 0.034). In multivariable analysis, blast count, TP53 mutations and number of mutations were independent predictors of OS, whereas the cytogenetic subgroups did not retain prognostic relevance. This study highlights the importance of mutational analysis in terms of prognosis in MDS patients with isolated -7 or del(7q).

Combination therapy with transcranial magnetic stimulation and ketamine for treatment-resistant depression: A long-term retrospective review of clinical use.

BACKGROUND: Both transcranial magnetic stimulation (TMS) and infused ketamine are recognized treatments for patients suffering from major depressive disorder (MDD). A novel therapy named combination TMS with ketamine (CTK) is introduced. This retrospective review examined the safety and clinical benefits of CTK in patients suffering from treatment-resistant depression (TRD) during the routine practice of psychiatry in a private clinic. METHODS: TRD patients (N = 28) received a coincident application of high-output TMS (30 minutes) with biomarker-determined ketamine infusions (20 minutes). Frequency of treatment was dependent on patient responsiveness (10-30 sessions). Clinical global impression (CGI) data was collected pre- and post-treatment and then two years later. RESULTS: The mean reduction in CGI severity for the patient group following CTK was 4.46 ± 0.54 at a 99% confidence interval and was deemed statistically significant using a paired t-test (α = 0.01, t = 22.81 p < 0.0001). This reduction was sustained for two years following treatment completion and this remission was deemed statistically significant by a second paired t-test (α = 0.01, t = 27.36, p < 0.0001). LIMITATIONS: Retrospective review of a limited number of patients undergoing CTK in a clinical practice. CONCLUSIONS: This clinical review indicated that CTK is an effective, long-term therapy (after two years) and can be used for TRD patients. The coincident administration of ketamine allowed for higher TMS intensities than otherwise would be tolerated by patients. Further studies for optimization of CTK are warranted.

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms.

Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3' telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants. Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.

Mixed T Cell Chimerism After Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Using an Alemtuzumab-Containing Regimen Is Shaped by Persistence of Recipient CD8 T Cells.

Prevention of graft-versus-host disease (GVHD) is paramount for allogeneic hematopoietic stem cell transplantation (HSCT) to treat nonmalignant diseases. We previously reported that allogeneic HSCT for severe aplastic anemia (SAA) using the fludarabine, cyclophosphamide, and alemtuzumab (Campath-1H) (FCC) regimen is associated with a very low risk of GVHD and excellent clinical outcomes. We now report a single-center study of 45 patients with longer follow-up and investigation of lymphocyte recovery. Overall survival (OS) was 93%, and event-free survival (EFS) was 90.7%. Acute and chronic GVHD each occurred in 6 patients (13.3%), and only 1 case was severe. Mixed T cell chimerism was frequent and persisted after cessation of immunosuppression. T cells were extensively depleted, representing only 11.3% of lymphocytes at day 30 and rising to 43.8% by 1 year, but still significantly below normal levels (67.2%; P = .018), and deficiency persisted after immunosuppressive therapy (IST) withdrawal. Depletion of CD4 T cells was particularly profound, causing inversion of the normal CD4:CD8 T cell ratio. T cell subset composition was also abnormal, with memory and effector T cells predominating for at least 6 months after FCC HSCT. Analysis of T cell subset chimerism showed that CD4 T cells were predominantly donor-derived at 1 year, whereas recipient-derived CD8 T cells shaped mixed chimerism with a notable contribution of recipient effector CD8 T cells. The prolonged mixed T cell chimerism after IST withdrawal and low incidence of GVHD indicates the establishment of mutual tolerance, but the low incidence of viral disease suggests maintenance of antiviral immunity. Our study shows that despite the abnormal T cell profile after allogeneic HSCT for SAA using the FCC regimen, this regimen is conducive to an excellent clinical outcome.

CSNK1A1 mutations and isolated del(5q) abnormality in myelodysplastic syndrome: a retrospective mutational analysis.

BACKGROUND: A mechanism for clonal growth advantage in isolated del(5q) disease remains elusive. CSNK1A1 resides on the critically deleted region, and deletion of this gene has been shown in mouse knockout and transplantation studies to produce some characteristics of bone marrow failure, including a proliferative advantage. We aimed to establish the frequency, nature, and clinical association of CSNK1A1 mutations in patients with myelodysplastic syndrome and associated myeloid neoplasms. METHODS: Between June 1, 2004, and May 31, 2014, in King's College (London, UK), we did whole-exome sequencing of five patients with isolated del(5q) followed by targeted screening for CSNK1A1 mutations and 20 myelodysplastic syndrome-associated mutations in 245 additional patients with myeloid neoplasms. All patients met present WHO diagnostic criteria for myelodysplastic syndrome and other related myeloid neoplasms. FINDINGS: 39 (16%) of 250 patients with myeloid neoplasms had isolated del(5q), of whom seven (18%) had CSNK1A1 mutations. All these mutations were missense and presented in a highly conserved region that is implicated in ATP catalysis. Serial sampling and response to lenalidomide treatment showed that CSNK1A1 mutations were highly associated with the del(5q) clone. Only one patient with a CSNK1A1 mutation showed complete cytogenetic response to lenalidomide. Four (57%) of the seven patients carrying a CSNK1A1 mutation showed disease progression coupled with an increase in mutant allele burden (all four were on lenalidomide). We detected coexisting myelodysplastic syndrome-related gene mutations in patients with CSNK1A1 mutations, including TP53. INTERPRETATION: Similar to the effect of TP53 mutations on progression of del(5q) abnormality, mutant CSNK1A1 also gives rise to a poor prognosis in del(5q) abnormality, for which a coupled increase in P53 activation is suggested. CSNK1A1 mutations in del(5q) disease are important in the context of therapeutic manipulation and need incorporation into future prospective studies. FUNDING: Leukaemia and Lymphoma Research.

Ketamine and transcranial magnetic stimulation treatment for bipolar II disorder: a case report.

INTRODUCTION: To the best of our knowledge, this is the first case report of successful treatment for bipolar II disorder using a combined ketamine and transcranial magnetic stimulation treatment. CASE PRESENTATION: A 43-year-old Caucasian unemployed man presented to us with treatment-resistant bipolar II disorder, currently in a mixed state. A psychometric assessment and brain single-photon emission computer tomography scan were conducted at baseline. His psychometric assessment revealed severe depressive and manic symptoms that were consistent with bipolar II disorder. Findings from a brain single-photon emission computer tomography scan converged with those from his psychometric assessment. The combined ketamine and transcranial magnetic stimulation treatment was administered a total of 24 times over five months, with his ketamine dosage increased from 50mg at the first treatment to 600 mg by the last. Starting after the second treatment, he reported substantial improvements in his symptoms. A follow-up psychometric assessment and brain single-photon emission computer tomography scan five months later revealed substantial blood flow increases in the previously deficient areas. CONCLUSIONS: We provide preliminary evidence for a treatment method that magnifies the therapeutic benefits of infused ketamine along with transcranial magnetic stimulation. We postulate that this may be based on an interaction at the level of the relevant cortico-thalamo-cortical circuit(s).

Combination therapy utilizing ketamine and transcranial magnetic stimulation for treatment-resistant depression: a case report.

In the present article, we report on the case of a 23-year-old woman with a history of treatment-resistant depression who achieved significant symptom improvement with a novel treatment consisting of ketamine, a dissociative anesthetic, and external neuromodulation with transcranial magnetic stimulation (TMS). This case highlights the need for further investigation of treatments pairing external neuromodulation with dissociative anesthetics.

The combined use of rhBMP-2/ACS, autogenous bone graft, a bovine bone mineral biomaterial, platelet-rich plasma, and guided bone regeneration at nonsubmerged implant placement for supracrestal bone augmentation. A case report.

This case report presents the clinical application and outcomes of the use of a combined approach to treat a patient with a severe alveolar defect. Recombinant human bone morphogenetic protein-2 in an absorbable collagen sponge carrier, along with autogenous bone graft, bovine bone mineral, platelet-rich plasma, and guided bone regeneration, were used simultaneous with nonsubmerged implant placement. At 1 year postsurgery, healthy peri-implant soft tissues and radiographically stable peri-implant crestal bone levels were observed along with locally increased radiographic bone density. In addition, a cone beam computed tomography (CBCT) scan demonstrated apparent supracrestal peri-implant bone augmentation with the appearance of normal alveolar ridge contours, including the facial bone wall.

Virtual rounding via videoconference-enabled smartphones: a case for multifacility rounds.

Telemedicine is defined as the use of medical information exchanged from one site to another via electronic communications to improve delivery of care. This improvement in delivery of care is evident by more-efficient consults, triaging, and real-time communication between patient and surgeon. Internet-capable smartphones are capable of transferring radiographs and other images. Aziz and Ziccardi in 2009 demonstrated using smartphones for downloading images from the hospital archiving system to the resident's phone and then e-mailing or texting them to the attending for immediate review. Here we build on the work of Aziz and Ziccardi as we describe a novel use of smartphones for virtual rounding between residents and faculty based on improvements in technology, specifically video capability and increased accessibility of compatible devices.

Sinus histiocytosis with massive lymphadenopathy Rosai-Dorfman disease: a unique case presentation.

Rosai and Dorfman first described sinus histiocytosis with massive lymphadenopathy (SHML) in 1969 with an article detailing 4 cases in which they differentiated this disease entity from the grouping of diseases categorized as histiocytosis X, where it was previously classified. Also known as Rosai-Dorfman disease (RDD), it is clinically characterized as massive, painless, bilateral, symmetric cervical lymphadenopathy, with fever and leukocytosis. An 11-year-old African American boy was referred to our clinic for extraction of a severely decayed tooth #30 and evaluation of a large right-sided neck mass. Initially, the patient had been seen by his general dentist who had diagnosed the mass as an odontogenic abscess. After 2 courses of different antibiotics, no changes in the mass were noted. Subsequently, the patient was sent to the emergency department where CT revealed multiple right-sided neck masses with the largest measuring 4 × 2 cm. The patient underwent an incisional biopsy by otolaryngology and a diagnosis of necrotic lymph tissue was made. Upon our examination, the carious tooth #30 was felt to be an incidental finding and fine-needle aspiration cytology of the largest mass was performed in 2 places. This also provided a diagnosis of necrotic lymph tissue. In concert with the patient and his mother, the decision was made to excise the mass because of psychosocial concerns. A massive right-sided lymph node attached to the submandibular gland was found and excised without complication. Histologic examination with S-100 stain confirmed a diagnosis of RDD. The patient healed well following surgery and has experienced no further lymphadenopathy. This case presentation and review of the literature is unique, as the patient presented with unilateral cervical lymphadenopathy only. Open biopsy and 2 fine-needle aspirations all returned as necrotic lymph tissue. Obtaining the correct diagnosis was additionally hampered by coincidental dental pathology on the affected side and final diagnosis was made only by excisional biopsy, which is not necessarily indicated in cases of RDD.