Pediatric-Patient-Registration: Fill & Download for Free

I am not afraid of that anymore because it happens more often. But never had any horrible experience of that.I can understand the state of the patients lying on dental chair. Sometimes they are afraid,anxious of dental work, that's why they are not able to understand the instructions properly .They are not doing that intentionally, so its better to instruct them again that they have to open their mouth wide to get the treatment done right.Pediatric patients do this alot, but I never get angry instead this makes me laugh. This happens alot while we are doing bite registration and jaw record, required for making a denture.So not only we are used to it but we also know when we are at risk :)

Brief Background on Anti-CD19 CAR-T ImmunotherapySo far, CAR-T immunotherapy has been most successful against CD19-positive tumors such as Acute lymphoblastic leukemia - Wikipedia (specifically B-ALL). CD19 is a cell surface molecule mainly expressed by mature B cells, meaning anti-CD19 CAR-T targets B cell tumors but also normal B cells. Despite considerable differences in CAR-T constructs used in different studies (1, 2, 3, 4), specificallydifferent short-chain variable fragments, scFv (the anti-CD19 antibody variable domain) that would be expressed on the CAR-T cell surface to bind to the CD19 expressed by the B cell tumor, anddifferent stimulating elements (CD28 or 4-1BB +/- CD3 ) that would get inserted into its cell membrane to signal within,so far anti-CD19 CAR-Ts have yielded impressive anti-tumor responses in relapsed or refractory populations. This is interpreted as a considerable advance since these were patients who'd failed standard therapies.Reversible Neurotoxicities as also Fatalities have occurred in various Anti-CD19 CAR-T Immunotherapy TrialsSince such studies began, different groups, including Juno, Novartis and Kite, testing CAR-T immunotherapy for B cell cancers have reported severe side effects including CRS or Cytokine release syndrome - Wikipedia and neurotoxicity as well as fatalities.CRS ranged from low-grade to high-grade fevers, muscle pain (myalgia) and severe hypotension (5).CNS (Central nervous system - Wikipedia) involvement is striking and unexpected since it occurred even in patients without disease in CNS. Neurotoxicity symptoms ranged from Ataxia - Wikipedia (lack of coordination), confusion and delirium to speech loss (aphasia), hallucinations, headaches, seizures (3, 4, 6, 7, 8, 9).While different studies reported anti-CD19 CAR-T associated-neurotoxicities in 13 to 53% of patients (10), they were reversible with speedy admission into critical care and aggressive management.Juno's ROCKET trial: Too Many Fatalities, All from Cerebral Edema. Why: Patient selection criteria and/or CAR-T construct and/or dose?Juno's ROCKET trial was different because it had far more fatalities and all from the same cause, cerebral edema, something previously unreported. Juno Therapeutics first reported 3 fatalities among enrolled patients with resistant/refractory B-ALL (11).Some additional background is necessary at this point. Early in tests of CAR-Ts, scientists observed that depleting patients of lymphocytes (aka lymphodepletion or conditioning) seemed to improve clinical response. Speculation is reducing patient's own circulating lymphocytes prior to infusing them with CAR-Ts reduces competition for cytokines such as IL-7 and IL-15 that CAR-Ts need to survive and expand. Accordingly, patients in Juno's ROCKET study also received conditioning consisting of Fludarabine - Wikipedia / Cyclophosphamide - Wikipedia, a nucleoside analog and an alkylating agent, respectively.FDA put this trial on hold after 3 patients died but then lifted the hold in a record short time, allowing it to resume after removing Fludarabine alone, implying it was the source of increased neurotoxicity. However, two more deaths occurred even after this modification in the conditioning regimen, which led to the FDA stopping this trial.It's difficult to decipher what led to these fatalities since all the relevant factors aren't (yet) in the public domain. However, comparing variables between different trials helps narrow down options (see below from 12) to patient selection and CAR-T construct and dose.Specifically, was there something different about their patient selection criteria and CAR-T construct, and did they use a different perhaps larger dose? This is becauseConditioning regimen of Fludarabine/Cyclophosphamide is commonly used in such trials with no reports of similar problems so that's out as a probable cause.Juno used autologous CAR-T cells (derived from patients themselves) as did Novartis and Kite.Juno used a similar CAR-T construct to the one currently being used by Kite in its anti-CD19 CAR-T trial (13). However, Juno tested it for ALL while Kite's ongoing trial is against non-Hodgkin's lymphoma (NHL). Safe in NHL (at least as of Aug 2017) but not in ALL patients would be an obvious speculation, and determining what the difference entails would be an obvious question to explore.Novartis (14) and Fred Hutchinson Cancer Research Center (15) are using a different CAR-T construct against ALL.Key difference is the signaling domain in their CAR-T is derived from 4-1BB while Juno and Novartis use one derived from CD28 (see below from 12).Studies suggest the CD28 signaling domain enhances anti-tumor activity (16) while the 4-1BB signaling domain confers longer persistence (16, 17).Though the Novartis (14) and FHCRC (15) trials are still ongoing, they already report high percentages of 82 (24 of 29) (18) and 93% (27 of 29) (19), respectively, complete response, which is disappearance of all clinical evidence of disease. No reports yet (as of Aug 2017) of fatalities due to cerebral edema.Unfortunately, patient selection criteria and CAR-T dose Juno used in their ROCKET trial aren't yet available in the public domain (as of Aug 2017) so conclusions about their role can only be speculative.Dose is an especially interesting consideration since one FHCRC study (19) done in collaboration with and funded by Juno showed a correlation between CAR-T cell dose and time of peak CAR-T expansion.What was additionally interesting about this study is that even though they infused CD4 and CD8 CAR-T cells at a 1:1 ratio, they found higher absolute numbers of CD8s at the peak of expansion.Since activated CD8 Cytotoxic T cell - Wikipedia are presumably the effector cells that actually kill the tumor cells, whether dose-dependent expansion of this type of 2nd generation CD8 CAR-Ts could contribute to cerebral edema in relapsing/refractory B-ALL at the dose Juno used in its ROCKET trial is a possibility to consider.Bibliography1. Grupp, Stephan A., et al. "Chimeric antigen receptor–modified T cells for acute lymphoid leukemia." New England Journal of Medicine 368.16 (2013): 1509-1518.; http://www.nejm.org/doi/pdf/10.1056/NEJMoa12151342. Kochenderfer, James N., et al. "Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation." Blood 122.25 (2013): 4129-4139. https://pdfs.semanticscholar.org/cf2b/c433b1f370d1471e4df435a8e618594e0b67.pdf3. Davila, Marco L., et al. "Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia." Science translational medicine 6.224 (2014): 224ra25-224ra25. https://www.researchgate.net/profile/Marco_Davila2/publication/260271032_Efficacy_and_Toxicity_Management_of_19-28z_CAR_T_Cell_Therapy_in_B_Cell_Acute_Lymphoblastic_Leukemia/links/55518f8d08ae739bdb921e51.pdf4. Lee, Daniel W., et al. "T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial." The Lancet 385.9967 (2015): 517-528. https://www.researchgate.net/profile/Rimas_Orentas/publication/266975072_T_cells_expressing_CD19_chimeric_antigen_receptors_for_acute_lymphoblastic_leukaemia_in_children_and_young_adults_a_phase_1_dose-escalation_trial/links/551ea0b30cf2a2d9e13c83d2/T-cells-expressing-CD19-chimeric-antigen-receptors-for-acute-lymphoblastic-leukaemia-in-children-and-young-adults-a-phase-1-dose-escalation-trial.pdf5. Lee, Daniel W., et al. "Current concepts in the diagnosis and management of cytokine release syndrome." Blood 124.2 (2014): 188-195. http://www.bloodjournal.org/content/bloodjournal/124/2/188.full.pdf?sso-checked=true6. Brentjens, Renier J., et al. "CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia." Science translational medicine 5.177 (2013): 177ra38-177ra38. https://www.researchgate.net/profile/Marco_Davila2/publication/236067161_CD19-Targeted_T_Cells_Rapidly_Induce_Molecular_Remissions_in_Adults_with_Chemotherapy-Refractory_Acute_Lymphoblastic_Leukemia/links/5551902808ae12808b392acd.pdf7. Maude, Shannon L., et al. "Chimeric antigen receptor T cells for sustained remissions in leukemia." New England Journal of Medicine 371.16 (2014): 1507-1517. http://www.nejm.org/doi/pdf/10.1056/NEJMoa14072228. Park, Jae H., et al. "Implications of minimal residual disease negative complete remission (MRD-CR) and allogeneic stem cell transplant on safety and clinical outcome of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed, refractory B-cell ALL." (2015): 682-682.9. Schuster, Stephen J., et al. "Sustained remissions following chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas." (2015): 183-183.10. Wang, Zhenguang, Yelei Guo, and Weidong Han. "Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment." Protein & Cell (2017): 1-30. https://link.springer.com/content/pdf/10.1007%2Fs13238-017-0400-z.pdf11. DeFrancesco, Laura. "Juno's wild ride." (2016): 793-793. https://www.nature.com/nbt/journal/v34/n8/full/nbt0816-793.html12. Hartmann, Jessica, et al. "Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts." EMBO Molecular Medicine (2017): e201607485. http://embomolmed.embopress.org/content/embomm/early/2017/07/31/emmm.201607485.full.pdf13. A Phase 1-2 Multi-Center Study Evaluating KTE-C19 in Subjects With Refractory Aggressive Non-Hodgkin Lymphoma (ZUMA-1)14. Determine Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell ALL15. Laboratory Treated T Cells in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, or Acute Lymphoblastic Leukemia - Full Text View - ClinicalTrials.gov16. Zhao, Zeguo, et al. "Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells." Cancer cell 28.4 (2015): 415-428. https://www.researchgate.net/profile/Maud_Condomines/publication/283205585_Structural_Design_of_Engineered_Costimulation_Determines_Tumor_Rejection_Kinetics_and_Persistence_of_CAR_T_Cells/links/5633886508ae88cf81ba47ac.pdf17. Porter, David L., et al. "Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia." Science translational medicine 7.303 (2015): 303ra139-303ra139. http://proaa9ff3.pic19.websiteonline.cn/upload/cart19+and+cll_dz87.pdf18. Grupp, Stephan A., et al. "Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL)." (2016): 221-221.19. Turtle, Cameron J., et al. "CD19 CAR–T cells of defined CD4+: CD8+ composition in adult B cell ALL patients." The Journal of clinical investigation 126.6 (2016): 2123. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887159/pdf/JCI85309.pdfThanks for the R2A, Christopher VanLang.

The most ridiculous policy I think is the $40 late fee charge. My daughter had this endocrinologist that had you sign at the initial registration that there would be a $40 late/ no show fee if any of the above applied. She specialized in pediatric endocrinology and only had hours between 9am and 1pm. When there was a scheduled appointment, I had to take my daughter during school hours ( appointments when school were out were for some reason always already filled). Not wanting to pay the late fee, I was always on time. The only thing was we would sit in the waiting room from 45 minutes to an hour and 10 minutes waiting to see the doctor. When my daughter was finally called in, like a broken record, she would always belt out: "sorry for the wait, a patient before was late and that threw the schedule off". This was every single appointment.So who pays the patient wheb rhey have to wait. Everyone's time is important, even if they aren't doctors. We stopped going there because on our return from thanksgiving vacation, the Sunday evening flight was delayed, and we were unable to make the Monday appointment. Called to reschedule ( office was closed, voicemail left). 24 hours notice was not given (for Monday appointments it's by noon on Friday). Received a bill for $40 and the doctor rescheduled my reschedule appointment. No winning here. If you are running a tight ship, the ship has to be tight all over. Everybody's time is important, not just yours lady.