AM ONC Report PEARLS 9/28: BRCA mutations, Ommaya reservoirs, and Primary CNS Lymphoma

Take-home point: for patients with s/sx of increased ICP and focal neurologic deficits, rule out emergent and urgent causes first – hemorrhage, herniation, hydrocephalus, stroke. Then, think about other causes, including recrudescence of old symptoms from metabolic or infectious insults!

GREAT PEARLS from the case:

  • BRCA mutations
    • BRCA1 and 2 are proteins important for repair of dsDNA breaks (via the error-free homologous recombinational repair (HRR) pathway). Therefore, a mutation can lead to errors in DNA repair, leading to cancer.
    • Patients with BRCA1 mutations do not have more aggressive cancers, but do have worse prognosis.
    • Targeted therapy: patients with BRCA1 mutations have increased response to platinum-based chemo and are great candidates for PARP inhibitors.
    • PARP inhibitor: poly-ADP ribose polymerase inhibitor. PARP1 is a protein that is involved in repairing single-strand breaks in DNA (which, if unrepaired, leads to double strand breaks). A PARP inhibitor causes multiple double strand breaks. In patients with BRCA mutations, because the double strand breaks can’t be efficiently repaired, cells die!
      • PARP inhibitors improve progression-free survival for women with recurrent platinum-sensitive ovarian cancer
    • For the visually-minded, here is a diagram!
    • PARP inhibitors
  • Ommaya reservoir: an intraventricular catheter system that allows easy access to CSF – for frequent delivery of drugs (esp chemo) as the blood-brain-barrier prevents penetration of many drugs, and for frequent removal of CSF for testing. This was initially invented for children with ALL (which commonly spreads to CNS).
    • However, there is a 30% risk of infection!
    • Another picture!
    • ommaya
  • Primary CNS lymphoma
    • An uncommon variant of extranodal non-Hodgkin lymphoma involving the brain, leptomeninges, eyes, or spinal cord, without evidence of systemic lymphoma!
    • Epidemiology:
      • Most commonly associated with immunodeficiency (HIV) however also now seen more and more in immunocompetent individuals
      • Mean age of onset is 55 years old in immunocompetent patients; 35yo for HIV+ patients
      • Men:Women (2:1)
    • Prognosis: rapidly fatal if untreated (1.5 mos!), however, treatment with high-dose methotrexate is quite effective (in combo with chemo) and prognosis of patients here at UCSF is up to 5-10 years!
      • For PCNSL recurrence: still can have 70% response to treatment!
      • Role of steroids? Initial response to steroids can be as high as 70%, however clinical improvement is usually transient, and disease tends to recur within a few months after discontinuation. Also can alter histopathology.
      • Role of whole brain radiation therapy? PCNSL is quite sensitive to this, however, there is an 80% risk of dementia and ADL dependence within 1 year if using 45Gy! So, with improved survival with chemo and poor side effect profile of WBRT, the latter is falling out of favor.
    • Diagnosis of leptomeningeal disease: CSF flow cytometry is more sensitive than cytology
  • Evernote: https://www.evernote.com/shard/s34/sh/539dbcca-b1ea-48df-8c89-efb4a15e727a/b90e6ed6649dc86b45d6bdbabf1a39ac
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