Impact of oncogene rearrangement patterns on outcomes in patients with double-hit non-Hodgkin lymphoma.

BACKGROUND: Double-hit lymphomas (DHLs) are collectively defined as B-cell non-Hodgkin lymphomas harboring rearrangements of MYC as well as B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6). To the authors' knowledge, the impact of specific oncogene rearrangements on outcomes of patients with DHL who are treated with immunochemotherapy has not been previously described. METHODS: The authors identified patients whose diagnostic tissue specimens underwent metaphase karyotyping or fluorescence in situ hybridization for MYC as well as both BCL2 and BCL6 rearrangements. Cohorts were defined by the presence (+) or absence (-) of rearrangements: MYC+/BCL2+/BCL6- (BCL2-DHL), MYC+/BCL2-/BCL6+ (BCL6-DHL), and MYC+/BCL2+/BCL6+ (triple-hit lymphoma; THL). RESULTS: A total of 117 patients were included in the current analysis (76 BCL2-DHL patients, 16 BCL6-DHL patients, and 25 THL patients). Compared with patients with BCL2-DHL, those with BCL6-DHL were more likely to be classified as having a non-germinal center cell of origin, presented with extranodal disease, and appeared to achieve higher rates of complete response despite receiving intensive induction therapy less frequently. However, patients with BCL6-DHL experienced a shorter median overall survival if achieving an initial complete response compared with patients with BCL2-DHL. Patients with THL experienced survival outcomes similar to those of patients with BCL2-DHL. CONCLUSIONS: Recognition of the specific oncogene rearrangements may be of prognostic value and potentially guide future therapeutic strategies for patients with DHL.

Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis.

Patients with double-hit lymphoma (DHL), which is characterized by rearrangements of MYC and either BCL2 or BCL6, face poor prognoses. We conducted a retrospective multicenter study of the impact of baseline clinical factors, induction therapy, and stem cell transplant (SCT) on the outcomes of 311 patients with previously untreated DHL. At median follow-up of 23 months, the median progression-free survival (PFS) and overall survival (OS) rates among all patients were 10.9 and 21.9 months, respectively. Forty percent of patients remain disease-free and 49% remain alive at 2 years. Intensive induction was associated with improved PFS, but not OS, and SCT was not associated with improved OS among patients achieving first complete remission (P = .14). By multivariate analysis, advanced stage, central nervous system involvement, leukocytosis, and LDH >3 times the upper limit of normal were associated with higher risk of death. Correcting for these, intensive induction was associated with improved OS. We developed a novel risk score for DHL, which divides patients into high-, intermediate-, and low-risk groups. In conclusion, a subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.

Single Center Outcomes of Status Epilepticus at a Paediatric Intensive Care Unit.

BACKGROUND: Status epilepticus (SE) is a frequent admission diagnosis to paediatric intensive care units (PICUs) and is associated with variable outcomes. We have audited our experience of patients presenting in SE at a Canadian PICU to determine unfavorable outcome variables. METHODS: Charts of patients <18 years of age presenting in SE to a tertiary care PICU over a 10-year period were audited. Data were analyzed at three care-points: transport, the emergency department (ED) and the PICU. Patient outcome before PICU discharge was categorized as "favorable" for return to pre-status functioning level or "unfavorable" for new deficit/death. Student's t-test and the Kruskal-Wallis test were used for analysis of normal and skewed continuous variables, respectively, and either Chi-square test or Fisher's exact test for categorical variables. RESULTS: 189 patients (54% males) were identified with a median age of 1.9 years. Idiopathic SE had the highest incidence; infectious/vascular etiologies were associated with more unfavorable outcomes. Progression to refractory SE in the ED had a higher incidence of death (p<0.05). Patients with an unfavorable outcome had a higher incidence of apnea during transport (p=0.01), longer hospital stays (p<0.05), need for therapeutic coma (p=0.01), longer duration of therapeutic coma (p<0.05), need for mechanical ventilation (p<0.05), and recurrent or refractory seizures during inpatient stay (p<0.05). Multivariate analysis of unfavorable outcomes of patients in SE presenting to the PICU included renal failure, cerebral edema, apnea during transport, refractory seizures, and recurrent seizures. CONCLUSIONS: Refractory seizures in children presenting with SE are associated with worsened outcomes in the PICU.

A phase 2 study of weekly temsirolimus and bortezomib for relapsed or refractory B-cell non-Hodgkin lymphoma: A Wisconsin Oncology Network study.

BACKGROUND: Proteasome inhibitors and mammalian target of rapamycin inhibitors each have activity in various B-cell malignancies and affect distinct cellular pathways. Their combination has demonstrated synergy in vitro and in mouse models. METHODS: The authors conducted a single-arm, phase 2 trial of combined temsirolimus and bortezomib in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (NHL) using a dosing scheme that was previously tested in multiple myeloma. The patients received bortezomib and temsirolimus weekly on days 1, 8, 15, and 22 of a 35-day cycle. RESULTS: Of 39 patients who received treatment, 3 achieved a complete response (7.7%; 95% confidence interval [CI], 1.6%-21%), and 9 had a partial response (PR) (23%; 95% CI, 11%-39%). Thus, the overall response rate (12 of 39 patients) was 31% (95% CI, 17%-48%), and the median progression-free survival was 4.7 months (95% CI, 2.1-7.8 months; 2 months for patients with diffuse large B-cell lymphoma [n = 18], 7.5 months for those with mantle cell lymphoma [n = 7], and 16.5 months for those with follicular lymphoma [n = 9]). Two extensively treated patients with diffuse large B-cell lymphoma achieved a complete response. There were no unexpected toxicities from the combination. CONCLUSIONS: The current results demonstrate that the combination of a mammalian target of rapamycin inhibitor and a proteasome inhibitor is safe and has activity in patients with heavily pretreated B-cell NHL. Further studies with this combination are warranted in specific subtypes of NHL.

An Immunologic Storm: A Case of Encephalitis and Thrombotic Thrombocytopenic Purpura With Underlying Likely Sjogren's Syndrome Induced by a COVID-19 Immune Response.

Introduction: There are rare cases of Sjogren's syndrome presenting with manifestations of encephalitis. There are also rare patients with Sjogren's presenting with acute thrombotic thrombocytopenic purpura (TTP). There are no cases of both occurring together as the only symptoms of the syndrome. During the COVID-19 pandemic, more cases of autoimmunity are being described given its robust immune response. It is important to keep a wide differential about these varying clinical presentations. Case Presentation: Our patient is a 19-year-old female with a history of menorrhagia, recent COVID-19 infection, and remote suicidal ideation. She presented with headaches, vomiting, and psychosis. Her labs found platelets of 12,000 and she was soon discovered to have TTP. She was found to have contrast enhancing lesions scattered in her left hemisphere on magnetic resonance imaging as well as seizures. Her workup was negative for infection, but labs revealed a positive antinuclear antibody, elevated anti-Ro antibody (anti-SSA) and anti-La antibody (anti-SSB), and elevated COVID-19 antibodies. She was treated with antiepileptics, pulse dose steroids for 5 days, plasmapheresis, and weekly rituximab for 4 weeks. She had significant clinical improvement. Conclusion: Sjogren's syndrome can have varying presentations including TTP with or without encephalitis as a presenting feature. Autoimmunity can also be triggered from COVID-19 infection.

Orientation of a bipolar membrane determines the dominant ion and carbonic species transport in membrane electrode assemblies for CO2 reduction.

A bipolar membrane (BPM), consisting of a cation and an anion exchange layer (CEL and AEL), can be used in an electrochemical cell in two orientations: reverse bias and forward bias. A reverse bias is traditionally used to facilitate water dissociation and control the pH at either side. A forward bias has been proposed for several applications, but insight into the ion transport mechanism is lacking. At the same time, when implementing a BPM in a membrane electrode assembly (MEA) for CO2 reduction, the BPM orientation determines the environment of the CO2 reduction catalyst, the anolyte interaction and the direction of the electric field at the interface layer. In order to understand the transport mechanisms of ions and carbonic species within a bipolar membrane electrode assembly (BPMEA), these two orientations were compared by performing CO2 reduction. Here, we present a novel BPMEA using a Ag catalyst layer directly deposited on the membrane layer at the vapour-liquid interface. In the case of reverse bias, the main ion transport mechanism is water dissociation. CO2 can easily crossover through the CEL as neutral carbonic acid due to the low pH in the reverse bias. Once it enters the AEL, it will be transported to the anolyte as (bi)carbonate because of the presence of hydroxide ions. When the BPM is in the forward bias mode, with the AEL facing the cathode, no net water dissociation occurs. This not only leads to a 3 V lower cathodic potential but also reduces the flux of carbonic species through the BPM. As the pH in the AEL is higher, (bi)carbonate is transported towards the CEL, which then blocks the majority of those species. However, this forward bias mode showed a lower selectivity towards CO production and a higher salt concentration was observed at the cathode surface. The high overpotential and CO2 crossover in reverse bias can be mitigated via engineering BPMs, providing higher potential for future application than that of a BPM in forward bias owing to the intrinsic disadvantages of salt recombination and poor faradaic efficiency for CO2 reduction.

Noninvasive Localization of Language Cortex in an Awake 4-Year-Old Child with Rasmussen Encephalitis: A Case Report.

BACKGROUND AND IMPORTANCE: Presurgical mapping of eloquent cortex in young patients undergoing neurosurgery is critical for timely intervention, surgical planning, and minimizing postoperative deficits. However, invasive direct cortical stimulation has limited success in young children and noninvasive modalities, such as magnetoencephalography and functional MRI, require sedation, often precluding localization of critical language cortices. Transcranial magnetic stimulation (TMS), a noninvasive brain stimulation technique, is well suited to evaluate language areas in young children because it does not require the patient to remain still during mapping. CLINICAL PRESENTATION: A 4-yr and 11-mo-old female patient diagnosed with epilepsia partialis continua of the right arm and face and right-sided weakness was evaluated at our institution. MRI findings and clinical examination led to the diagnosis of Rasmussen encephalitis involving left frontal lobe and insula. Language cortices were successfully identified in both hemispheres using TMS. The TMS findings aided in discussing with the family the risks of postsurgical deficits of left functional hemispherectomy, the definitive treatment for Rasmussen encephalitis. Postoperatively, the patient had intact speech and was seizure free. CONCLUSION: We illustrate the feasibility and utility of TMS as a noninvasive functional mapping tool in this young child. The preoperative demonstration of bilateral language organization indicated a greater likelihood of preserved language functions postsurgery. We demonstrate that TMS is a safe and noninvasive tool to map language cortices in young children with serious epilepsy syndromes.

Effect of Routine Surveillance Imaging on the Outcomes of Patients With Classical Hodgkin Lymphoma After Autologous Hematopoietic Cell Transplantation.

BACKGROUND: Patients with relapsed and refractory classical Hodgkin lymphoma (cHL) are often treated with autologous hematopoietic cell transplantation (auto-HCT). After auto-HCT, most transplant centers implement routine surveillance imaging to monitor for disease relapse; however, there is limited evidence to support this practice. PATIENTS AND METHODS: In this multicenter, retrospective study, we identified cHL patients (n = 128) who received auto-HCT, achieved complete remission (CR) after transplantation, and then were followed with routine surveillance imaging. Of these, 29 (23%) relapsed after day 100 after auto-HCT. Relapse was detected clinically in 14 patients and with routine surveillance imaging in 15 patients. RESULTS: When clinically detected relapse was compared with to radiographically detected relapse respectively, the median overall survival (2084 days [range, 225-4161] vs. 2737 days [range, 172-2750]; P = .51), the median time to relapse (247 days [range, 141-3974] vs. 814 days [range, 96-1682]; P = .30) and the median postrelapse survival (674 days [range, 13-1883] vs. 1146 days [range, 4-2548]; P = .52) were not statistically different. In patients who never relapsed after auto-HCT, a median of 4 (range, 1-25) surveillance imaging studies were performed over a median follow-up period of 3.5 years. CONCLUSION: A minority of patients with cHL who achieve CR after auto-HCT will ultimately relapse. Surveillance imaging detected approximately half of relapses; however, outcomes were similar for those whose relapse was detected using routine surveillance imaging versus detected clinically in between surveillance imaging studies. There appears to be limited utility for routine surveillance imaging in cHL patients who achieve CR after auto-HCT.

Postictal psychosis in a child.

Postictal psychosis is a state of psychosis following repeated or prolonged complex partial seizures with or without secondary generalization and is well described in adult epilepsy literature. It is sparsely reported in the pediatric literature. This report describes a 12-year-old male presenting with status epilepticus who developed psychotic symptoms. Diagnosis of postictal psychosis was made after correlating clinical symptoms with video-electroencephalographic monitoring. The clinical course of this illness is profiled, and the literature reviewed.

Severe Neurological Complications Associated With Tourette Syndrome.

BACKGROUND: Tics and Tourette syndrome are common problems evaluated by both the general pediatrician and pediatric neurologist. The common comorbidities of tics are well known, but the severe neurological complications are rare and may not be appreciated. METHODS: This is a retrospective case series and literature review. RESULTS: We present here four adolescents with Tourette syndrome who had severe neurological complications secondary to motor tics. We provide the history, neurological examination, and radiological findings in addition to a review of previously reported cases of vascular and cervical cord complications associated with violent motor tics. CONCLUSIONS: We highlight the importance of recognizing the presenting signs of these complications early and the need to vigorously treat violent motor tics to prevent significant neurological complications.

Chronological Evolution of Magnetic Resonance Imaging Findings in Children With Febrile Infection-Related Epilepsy Syndrome.

OBJECTIVE: To describe and analyze the chronological evolution of the radiological findings in seven children with febrile infection-related epilepsy syndrome. METHODS: This is a retrospective study describing the radiological findings and evolution in seven children with febrile infection-related epilepsy syndrome who presented from 2009 to 2013. The children all fit the defined clinical criteria for febrile infection-related epilepsy syndrome; all had a history of normal psychomotor development who presented with acute-onset catastrophic partial status epilepticus associated with a febrile illness or unspecific infectious process. The children were identified from the author's weekly review of the pediatric inpatient service, and then the data were collected and analyzed retrospectively. RESULTS: Six males and one female ranging from 3 months to 9 years of age presented with status epilepticus preceded by a febrile illness. Extensive investigations for infectious, autoimmune, and metabolic etiologies were unremarkable. Multiple antiepileptic medications were attempted, including drug-induced coma in all of them, with poor response. Immunotherapy with intravenous steroids or intravenous immunoglobulin (three patients had both) was tried in six of seven patients with a poor response. Ketogenic diet was initiated in four of seven patients with limited response. Serial magnetic resonance imaging studies, done from the initial presentation through 18 months of follow-up, showed evolution from normal imaging to severe cerebral atrophy. Progressive cytotoxic edema involving mostly bilateral hippocampi and temporal lobes was appreciated in one to three weeks. At one month from seizure onset, mild to moderate cerebral atrophy and hippocampal sclerosis was appreciated that continued to progress over the next year. After six to twelve months, most of the patients showed moderate to severe cerebral atrophy and by one year, cerebellar atrophy was also appreciated. CONCLUSION: Febrile infection-related epilepsy syndrome is a devastating epilepsy syndrome of childhood without a diagnostic biologic marker. The magnetic resonance imaging findings appear to be progressive and typical. Thus, combined with the clinical course, imaging findings can help to confirm the diagnosis (until a biologic marker is found). This hopefully will allow multicentered treatment protocols in the future.

Impact of Routine Surveillance Imaging on Outcomes of Patients With Diffuse Large B-Cell Lymphoma After Autologous Hematopoietic Cell Transplantation.

BACKGROUND: For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), autologous hematopoietic cell transplantation (auto-HCT) is commonly used. After auto-HCT, DLBCL patients are often monitored with surveillance imaging. However, there is little evidence to support this practice. PATIENTS AND METHODS: We performed a multicenter retrospective study of DLBCL patients who underwent auto-HCT (n = 160), who experienced complete remission after transplantation, and who then underwent surveillance imaging. Of these, only 45 patients experienced relapse after day +100 after auto-HCT, with relapse detected by routine imaging in 32 (71%) and relapse detected clinically in 13 (29%). RESULTS: Baseline patient characteristics were similar between the 2 groups. Comparing the radiographic and clinically detected relapse groups, the median time from diagnosis to auto-HCT (389 days vs. 621 days, P = .06) and the median follow-up after auto-HCT (2464 days vs. 1593 days P = .60) were similar. The median time to relapse after auto-HCT was 191 days in radiographically detected relapses compared to 492 days in clinically detected relapses (P = .35), and median postrelapse survival was 359 days in such patients compared to 123 days in patients with clinically detected relapse (P = .36). However, the median posttransplantation overall survival was not significantly different for patients with relapse detected by routine imaging versus relapse detected clinically (643 vs. 586 days, P = .68). CONCLUSION: A majority (71%) of DLBCL relapses after auto-HCT are detected by routine surveillance imaging. Overall, there appears to be limited utility for routine imaging after auto-HCT except in select cases where earlier detection and salvage therapy with allogeneic HCT is a potential option.

Mitochondrial disorders: a potentially under-recognized etiology of infantile spasms.

Infantile spasms represent an age-dependent response of the immature brain to a wide variety of insults. An unselected group of children with infantile spasms were reviewed to determine etiology; a metabolic work-up was undertaken if the etiology was unclear from history and examination (cryptogenic). Of the 56 infants, 34 had a recognizable etiology (symptomatic), 1 had normal development (idiopathic), and 21 had cryptogenic infantile spasms. Among the latter, results of plasma lactate and pyruvate or urine organic acids were available in 17. In 2 infants (monozygotic twins), mitochondrial DNA testing revealed the relatively common A3243G mitochondrial mutation. In these twins and 11 of the remaining 15, body fluid metabolite testing suggested possible defective energy metabolism. Our twins and previous reports suggest that mitochondrial disorders should be considered in the differential diagnosis of infantile spasms. Among our cases remaining cryptogenic, signs of abnormal energy metabolism were prevalent, suggesting that metabolic derangements may be common causes or secondary consequences of infantile spasms.

Vigabatrin for infantile spasms.

We reviewed 20 infants receiving vigabatrin for infantile spasms. Patients were not enrolled in a formal study. All families obtained the medication abroad. Age at initiation of vigabatrin ranged from 1 to 48 months; nine infants had received prior treatment with various antiepileptic medications. Patients were begun on the lowest practical dose of 125-250 mg/day, with gradual daily increments to a target of 100 mg/kg/day, but maintained at the lowest effective dosage. Video electroencephalogram was obtained to document resolution of spasms and hypsarrhythmia. Of 20 infants, 12 responded with cessation of spasms and resolution of hypsarrhythmia, at doses of 25-135 mg/kg/day (median = 58 mg/kg/day). Partial responses were observed in six patients, whereas two had no response at 111 and 125 mg/kg/day. Additional new seizure types developed in three infants after initial response to vigabatrin. Increasing the vigabatrin did not have any clinical benefit. Vigabatrin is an effective, well-tolerated treatment for infantile spasms. The response is dose-independent, suggesting that starting at a low dose and gradually increasing, rather than beginning with an arbitrary 100 mg/kg/day dose is advantageous.

An adult male with progressive spastic paraparesis and gait instability.

This is a case of an adult male with history of motor difficulties, speech, and behavioral problems since early childhood found to have progressive spastic paraparesis, impaired vibration and proprioception, and gait instability. His medical history included bilateral cataracts status post surgical removal at the age of 30, cholelithiasis status post cholecystectomy at age 45, and high cholesterol levels.

The ketogenic diet for the treatment of myoclonic astatic epilepsy in a child with type 1 diabetes mellitus.

Initiation of the ketogenic diet in a child with epilepsy and type 1 diabetes mellitus presents a challenge because the distinction between diet-induced ketosis and diabetic ketoacidosis is difficult to discern. We report the successful use of the ketogenic diet in a child with myoclonic astatic epilepsy and type 1 diabetes.

Acute permethrin neurotoxicity: Variable presentations, high index of suspicion.

Permethrin is a synthetic Type I pyrethroidal neurotoxic pesticide that has been responsible for accidental animal deaths. Despite its widespread use, there are no published case reports on pediatric intensive care unit admissions due to permethrin exposure. We report the unusual and varied presentations of permethrin toxicity in three siblings presenting to a tertiary care pediatric intensive care unit (PICU). While there is no standard clinical diagnostic test for permethrin, accurate diagnosis was obtained by rapidly analyzing the offending agent. In the absence of a known antidote for permethrin, supportive management was initiated and resulted in a favorable outcome for all three siblings.

Comparison of ropivacaine and bupivacaine with fentanyl for caudal epidural in pediatric surgery.

CONTEXT: Ropivacaine, s-enantiomer of amide local anaesthetic produces differential neural blockade with less motor blockade, cardiovascular and neurological toxicity makes it suitable for day case surgery in children. AIMS: To compare the effectiveness of Inj. Ropivacaine (0.2 or 0.25%) or Inj. Bupivacaine (0.25%) with fentanyl in caudal block for intra and postoperative analgesia. SETTINGS AND DESIGN: Double blind retrospective randomized study. MATERIALS AND METHODS: All the patients (n=112) varying from age group 3.02 ± 3.29 years belonging to ASA I-IV were randomly allocated to receive caudal analgesia Group BF inj. Bupivacaine (0.25%, 2 mg/kg) + Inj. Fentany1 µg/kg (n=70) and group RF: Inj. Ropivacaine (0.25% or 0.2%, 2 mg/kg) + inj. Fentanyl 1 µg/kg (n=42). We monitored vitals and requirement of inhalational gases inraoperatively and also observed pain by pain score (Visual Analogue Score in verbal group and Objective Pain Scale in nonverbal group) and vitals postoperatively. We used rescue analgesics (inj. Paracetamol 5 mg/kg iv) when VAS score ≥4. STATISTICAL ANALYSIS: Student's t-test. RESULTS: Duration of analgesia was prolonged in both group RF and BF. Time for first rescue analgesic for group RF (6.1 ± 1.1 hr) compared to group BF (5.6 ± 0.9 hr). Haemodynamic stability and less requirement of inhalation agent intraoperatively with group RF than others. CONCLUSIONS: Ropivacaine with Fentanyl found to be better combination for pediatric surgeries for below umbilical surgeries as an adjuvant to general anaesthesia or sole technique with chances of less complication with high success rate.

A clinico-radiographic analysis of sagittal condylar guidance determined by protrusive interocclusal registration and panoramic radiographic images in humans.

PURPOSE: To evaluate the correlation between sagittal condylar guidance obtained by protrusive interocclusal records and panoramic radiograph tracing methods in human dentulous subjects. MATERIALS AND METHODS: The sagittal condylar guidance was determined in 75 dentulous subjects by protrusive interocclusal records using Aluwax through a face bow transfer (HANAU™ Spring Bow, Whip Mix Corporation, USA) to a semi-adjustable articulator (HANAU™ Wide-Vue Articulator, Whip Mix Corporation, USA). In the same subjects, the sagittal outline of the articular eminence and glenoid fossa was traced in panoramic radiographs. The sagittal condylar path inclination was constructed by joining the heights of curvature in the glenoid fossa and the corresponding articular eminence. This was then related to the constructed Frankfurt's horizontal plane to determine the radiographic angle of sagittal condylar guidance. RESULTS: A strong positive correlation existed between right and left condylar guidance by the protrusive interocclusal method (P 0.000) and similarly by the radiographic method (P 0.013). The mean difference between the condylar guidance obtained using both methods were 1.97° for the right side and 3.18° for the left side. This difference between the values by the two methods was found to be highly significant for the right (P 0.003) and left side (P 0.000), respectively. The sagittal condylar guidance obtained from both methods showed a significant positive correlation on right (P 0.000) and left side (P 0.015), respectively. CONCLUSION: Panoramic radiographic tracings of the sagittal condylar path guidance may be made relative to the Frankfurt's horizontal reference plane and the resulting condylar guidance angles used to set the condylar guide settings of semi-adjustable articulators.