Paed Haem Onc ClinLog

Question 1

Paed Onc Sept 2015

Answer 1

Learning points:

• 7yr old boy with undifferentiated mediastinal sarcoma on PICU who initially presented with an effusions, which was diagnosed as empyema. When it was drained did not appear purulent, low WCC, grew nothing. Was seen several times at local hospital with recurrent symptoms, no CXRs done. When re-attended for follow-up clinic was sytemically unwell, hunched over with resp distress, had huge mediastinal tumour occupying half of chest. Required treatment based on PICU with tracheostomy, difficult airway to maintain. Poor outlook. Potential learning points for tertiary centre:
  
  • If suspected empyema fluid does not look typical of pus, even if child has been on antibiotics for some time, it is worth sending cytology and booking earlier follow-up.
  • Oncology learning point: Undifferentiated sarcomas ‘NOS’ are generally treated with protocol based on iphosphamide (or cyclophosphamide) + doxorubicin backbone (like RMS).
  • Outstanding questions: What sort of molecular/genetic work-up is done for these children? Are there any basket studies of targeted agents that such information would allow patients to access in the UK? BET inhibitors in NUT midline carcinoma….
• 15F with high-risk ALL on Regimen C who developed inter-sphincteric fistula after severe infectious colitis and gram negative sepsis. Presented with recurrent severe gram negative sepsis and rectal pain/severe pain on defecation for 8 weeks. MRI was diagnostic.
  
  • Treatment options: seton suture; surgical closure would compromise faecal continence due to intersphincteric location of fistula. Given immunosuppression, seton suture not to be tightened as unlikely to heal - aim of treatment being to keep fistula open to allow pus to drain.
  • Symptomatic releif for fistulas: topical glyceryl trinitrate ointment to relax painful muscle spasm/dilate blood vessels and promote healing. Opposite mechanisms of action of most haemorrhoid preparations, which could theoretically be harmful in this situation (and long term use of topical anaesthetic not advised as sensitises cutaneous/mucosal pain receptors).
  • Further issue: new onset of recurrent vomiting not associated with nausea, very different from previous experience of vomiting; also complaining of ‘stabbing’ RUQ/epigastric pain. Need to consider stress ulcers/PUD ?would benefit from endoscope.
• Micro meeting learning points:
  
  • Never safe to keep line in when S. aureus cultured due to risk of seeding bone, heart valves, etc. If child well, line out followed by 2 weeks IV fluclox (if sensitive).
  • Meropenem and metronidazole are audited as duplicate therapy in the absence of C. difficile.
  • If an apparently drug-resistant Acinetobacter/other resistant Gram negative is isolated, need to do a CEP (carbapenemase) screen.
• Relapsed AML:
  
  • FLAG-IDA (fludarabine, G-CSF, Ara-C and Idarubicin) is standard second-line chemotherapy followed by transplant.
• 6yr old with large left renal mass and evidence of sub-capsular rupture.
  
  • Safety measure: immediate G&S given risk of bleeding into tumour or peritoneum
  • Biopsy contra-indicated with subcapsular rupture -> given characteristic age and radiological appearance of Wilm’s, plan for VA neo-adjuvant chemotherapy and surgery in approx 4-5 weeks.
• 11F with warm (IgG-mediated) autoimmune haemolytic anaemia.
  
  • Presented with 1 day history of breathlessness on mild exertion, followed the next day by noticeable jaundice -> admission to local hospital. At local hospital, FBC, LFT, U&E, DAT and U&E notable for Hb 53, increased RDW, normocytosis, slightly raised bilirubin, DAT positive for IgG 3+ coated red cells. Treated with IV ceftriaxone due to E. coli in MSU and with oral clarithromycin for mycoplasma cover (though mycoplasma is associated with cold (IgM-mediated) autoimmune haemolytic anaemia) and folic acid. Hb failed to increment after 2 units of packed cells, and patient was transferred for IVIG +/- methylpred. Hb fell to 46 by the end of the IVIG infusion, and she was transfused.
  • Had a mild reaction to IVIG requiring hydrocortisone and piriton. IVIG infusion was successfuly restarted at the same rate and gradually sped up.
  • General learning points re autoimmune haemolysis in children:
    
    • Usually acute and self-limiting
    • DAT is 90-95% sensitive for AIHA (IAT also positive in about 80%)
    • Most paediatric AIHA is warm (IgG-mediated), which is extravascular (splenic)
    • Warm AIHA can be due to viruses, drugs, autoimmune or malignant conditions.
    • Evan’s syndrome is when DAT +ve haemolytic anaemia is a/w autoimmune thrombocytopaenia.
• Neonate with trisomy 21 and TAM on ICU. Responded very well to low dose cytarabine (POG protocol).
  
  • Generally, once WCC starts to fall, continues to fall even with disconinuation of chemotherapy
  • Further cytarabine only indicated if WCC>50
• CSF leaks post-op often a/w hydrocephalus and the need for a shunt.
• Children with sickle cell disease are now routinely offered genotyping rather than only blood phenotyping in order to optimally match blood for them and reduce the risk of alloimmunisation.
• 15-month-old presenting with bleeding tendency an strong maternal family history of von Willebrand disease. Learning points included:
  
  • Taking a bleeding history of patient and affected family members
  • Family pedigree
  • Classification of von Willebrand disease and initial work-up
  • Remembering to advise not to use non-steroidals for fever/pain
  • Role of the CNS in liaising with nurseries, school and counseling guardians
  • Evidence for tranexamic acid

Question 2

CCLG BMT Study Day 18/06/2015

Answer 2

• Issues to consider when deciding on the appropriate source of stem cells for BMT:
  
  • Bone marrow transplants result in less GVHD but are of limited volume
  • Peripheral blood stem cell harvests yield larger volume but bring a higher risk of GVHD due to increased numbers of contaminating T-lymphocytes.
  • Cord blood is immediately available and theoretically requires less close matching (idea being that neonatal T cells are more tolerant). Further, cord blood banks better reflect the ethnic diversity of the patient population.
• Donor choice:
  
  • Tissue type matching is done based on molecular typing at 10 HLA-I and 10 HLA-II antigen.
  • CMV status – a positive CMV donor for a positive CMV recipient ensures that CMV immunity is also transplanted
  • Preferable to have a young male donor of the same blood group
• Principles of conditioning
  
  • In order for engraftment to occur, the haematopoietic stem cell niche must not be occupied by host HSCs. Myeloablation overcomes this (not needed in aplastic anaemia).
  • Conditioning therapy aims to eliminate host bone marrow (create space) and eliminate host immunity (prevent rejection)
  • Main cause of BMT-related death is the conditioning regiment and resulting infections.
    
    • Addressing toxicity: patient selection, intensity of conditioning.
    • Addressing infection: antimicrobial prophylaxis, screening for CMV/HSV reactivation, patient isolation, filter air, etc.
    • Two strategies to infectious complications when the do arise:
      
      • reduce immunosuppression, use graft vs infection
      • give antimicrobials.
• Immune action of graft: GVHD, graft vs leukaemia, graft vs infection.
• Clinical governance framework for BMT – standardising practice, rapid second opinions, frequent national MDTs and M&Ms.

GENE THERAPY VIA BMT

• Use of lentiviruses to correct enzyme deficiency and harness GVL and suppress GVHD
• Gene therapy risk – insertional mutagenesis. Was an issue with previous vectors that used to insert in dividing cells, which have switched on genes a/w growth and proliferation, and vectors tended to disrupt these genes. Lentiviral vectors insert randomly, reduce risk. Some risks of transplant also there. Cost.

GvHD – Kanchan Rau

• Definition McDonald et al 1986
• Accounts for 20% of allogeneic SCT mortality
• Inflammation’s role in GvHD, exacerbation by viruses, etc
• Timing of GvHD – acute, chronic, late onset acute GvHD
• Risk factors. Recipient factors – age, infection. Donor factors – degree of mismatch, female donor and male recipient. Graft factors – PBSC vs BM, T cell depletion/dose, GVHD prophylaxis, nature of conditioning
• Classical targets of GvHD: skin (early), GIT, liver (later, jaundice with cholestatic LFTs)
• Diagnosis of exclusion. CRP tends to be low. Viral PCRs, skin biopsy…
• Prevention: T cell depletion (in vitro with campath 1M or CD34 selection, in vivo with campath 1H, ATG). Most UK units use T-replete grafts for sibs and T depletion for MUD (in vivo) – US uses T-replete MUDs, no difference. T depletion mandatory for hapos. Balanced GVHD with GVL and graft failure.
• Prevention: ciclosporin, MMF, sirolimus, tacrolimus, Cya +MTX…
• GVHD treatment: steroids cornerstone
• Latest classification for acute GVHD is based on appearance, not timing…