The use of andexanet alfa vs. 4-factor prothrombin complex concentrates in the setting of life-threatening intracranial hemorrhage.

OBJECTIVE: Andexanet alfa is a targeted reversal agent for life threatening hemorrhage associated with direct acting oral anticoagulants (DOACs), but there is uncertainty regarding the benefit when compared to 4-factor prothrombin complex concentrate (4F-PCC) for this indication. We investigated the clinical outcomes and cost associated with reversal of DOACs in the setting of life-threatening intracranial hemorrhage (ICH). METHODS: A retrospective evaluation was conducted to evaluate patients with ICH in the setting of anticoagulation with DOAC from 9/1/2013 to 4/30/2020. Patients were included in the study if they received reversal with either andexanet alfa or 4F-PCC. RESULTS: Eighty-nine patients were included in the study. There was no statistically significant difference in 30-day mortality between patients who received andexanet alfa or 4F-PCC (52% vs. 35%, P  = 0.14). Radiographic stability of bleed was identified in 57% of patients receiving andexanet alfa vs. 58% of patients receiving 4F-PCC ( P  = 0.93). Median length of stay was not different between the andexanet alfa and 4F-PCC populations (7 days [IQR 6 - 12] vs. 6 days [IQR 3-12], P  = 0.66). Median cost of reversal agent was higher in patients receiving andexanet alfa compared to 4F-PCC ($15 000 [IQR 15 000-$27 000] vs. $11 650 [IQR $8567-$14 149]). CONCLUSION: Among patients with life-threatening intracranial hemorrhage in the setting of DOAC therapy, no clinical differences were observed with respect to selection of reversal agent. Prothrombin complex concentrates remain a viable alternative to reversal of DOAC therapy though multicenter, randomized, prospective studies are needed to further evaluate the role of 4F-PCC in the reversal of DOAC therapy.

Extramedullary Hematopoiesis in Mismatch Repair Deficient Colon Cancer Patient on Adjuvant Chemotherapy.

A 59-year-old male presented with a two-month history of abdominal pain and was found to have an obstructing cecal mass. Colonoscopy and biopsy confirmed invasive adenocarcinoma. Immunohistochemical analyses for mismatch repair (MMR) proteins revealed the loss of MLH1 as well as PMS2 in cancerous nuclei, which makes the tumor MMR deficient. Negative germline testing for MMR proteins ruled out the Lynch syndrome. After negative staging computerized tomography scan for distant metastases, he underwent ileocolectomy with ileotransverse colonic anastomosis. Final pathological analysis revealed poorly differentiated adenocarcinoma with signet ring features, negative margins, and 3/22 lymph nodes positive, classified as stage IIIB (T4aN1bM0). Adjuvant chemotherapy with modified FOLFOX (leucovorin calcium/folinic acid, fluorouracil, and oxaliplatin) was started without the use of any growth factor support. After cycle 9 of 12, he developed mild transaminitis, carcinoembryonic antigen elevation, and interval development of two heterogeneously enhancing hepatic lesions. Biopsy of both of these lesions revealed extramedullary hematopoiesis (EMH), with no evidence of metastatic disease. He completed adjuvant chemotherapy without complication, and these liver lesions have decreased in size during the follow-up period of almost two years thus far. EMH is extremely rare in patients with colon cancer. Contributing factors include therapy-specific (growth factor support), bone marrow suppression secondary to chemotherapy and radiation therapy, and tumor-specific factors (cytokine and growth factors released by the tumor). To the best of our knowledge, this is the first case report of EMH in an MMR deficient colon cancer patient on adjuvant FOLFOX. MMR-deficient tumors show signs of a high degree of infiltration with CD8+ cytotoxic T lymphocytes as well as helper T cells, leading to increased production of cytokines, such as interferon-γ. This could be a potential etiology behind EMH in our patient who was MMR deficient. The role of the MMR-deficient state in the development of EMH should be explored further.

The effects of new or worsened postoperative neurological deficits on survival of patients with glioblastoma.

OBJECTIVE An increased extent of resection (EOR) has been shown to improve overall survival of patients with glioblastoma (GBM) but has the potential for causing a new postoperative neurological deficit. To investigate the impact of surgical neurological morbidity on survival, the authors performed a retrospective analysis of the clinical data from patients with GBM to quantify the impact of a new neurological deficit on the survival benefit achieved with an increased EOR. METHODS The data from all GBM patients who underwent resection at the University of Florida from 2010 to 2015 with postoperative imaging within 72 hours of surgery were included in the study. Retrospective analysis was performed on clinical outcomes and tumor volumes determined on postoperative and follow-up imaging examinations. RESULTS Overall, 115 patients met the inclusion criteria for the study. Tumor volume at the time of presentation was a median of 59 cm3 (enhanced on T1-weighted MRI scans). The mean EOR (± SD) was 94.2% ± 8.7% (range 59.9%-100%). Almost 30% of patients had a new postoperative neurological deficit, including motor weakness, sensory deficits, language difficulty, visual deficits, confusion, and ataxia. The neurological deficits had resolved in 41% of these patients on subsequent follow-up examinations. The median overall survival was 13.1 months (95% CI 10.9-15.2 months). Using a multipredictor Cox model, the authors observed that increased EOR was associated with improved survival except for patients with smaller tumor volumes (≤ 15 cm3). A residual volume of 2.5 cm3 or less predicted a favorable overall survival. Developing a postoperative neurological deficit significantly affected survival (9.2 months compared with 14.7 months, p = 0.02), even if the neurological deficit had resolved by the first follow-up. However, there was a trend of improved survival among patients with resolution of a neurological deficit by the first follow-up compared with patients with a permanent neurological deficit. Any survival benefit from achieving a 95% EOR was abrogated by the development of a new neurological deficit postoperatively. CONCLUSIONS Developing a new neurological deficit after resection of GBM is associated with a decrease in overall survival. A careful balance between EOR and neurological compromise needs to be taken into account to reduce the likelihood of neurological morbidity from surgery.