RESUMO
Leptomeningeal metastasis/leptomeningeal carcinomatosis (LMC; terms used interchangeably) is an inflammatory complication of primary tumors that involves the spread of the disease to the meninges (specifically the arachnoid and pia maters) and spinal cord. In the United States, approximately 110,000 new cases are diagnosed each year, and the prognosis is usually poor. Complications of LMC include cognitive impairment, cranial nerve dysfunction, ischemic stroke, and mortality. The survival times of untreated and treated LMC are approximately 4-6 weeks and 2-4 months, respectively. Leptomeningeal carcinomatoses are usually metastatic cancers that spread to the central nervous system. Although lung and breast cancers have a clearly defined relationship with LMC, it remains unclear whether prostate cancer (PC) is also directly associated with LMC. To determine whether such association exists, we conducted a PubMed review of the literature on patients with PC with coexisting LMCs. Our search yielded 23 case reports of patients with preexisting PC who developed LMC. In addition, 2 retrospective cohort studies were examined. Various findings were identified in the revised cases and studies. The first 3 findings were related to the progression of the disease: patients presenting with neurological disease symptoms were in remission from PC for 7 years on average, LMCs tended to occur after other cancer diagnoses, and the disease had already rapidly progressed by the time the symptoms were present. Regarding diagnosis, the major finding was that most LMCs were detected by magnetic resonance imaging (which does not detect early dissemination), and it was suggested that single-photon emission computed tomography or positron emission tomography imaging could be used for earlier detection. Finally, in terms of treatment, the main finding was that treatment was palliative rather than curative and that prognosis remained poor despite treatment. On the basis of these results, we recommend for individuals with risk factors, such as high-grade PC and hormonal PC, to be evaluated on a case-by-case basis for increased surveillance of LMC development.
RESUMO
PURPOSE: Patients with glioblastoma (GBM) are treated with radiotherapy (RT) and temozolomide (TMZ). These treatments may cause prolonged systemic lymphopenia, which itself is associated with poor outcomes. NT-I7 is a long-acting IL7 that expands CD4 and CD8 T-cell numbers in humans and mice. We tested whether NT-I7 prevents systemic lymphopenia and improves survival in mouse models of GBM. EXPERIMENTAL DESIGN: C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day × 5 days), TMZ (33 mg/kg/day × 5 days), and/or NT-I7 (10 mg/kg on the final day of RT). We followed the mice for survival while serially analyzing levels of circulating T lymphocytes. We assessed regulatory T cells (Treg) and cytotoxic T lymphocytes in the tumor microenvironment, cervical lymph nodes, spleen, and thymus, and hematopoietic stem and progenitor cells in the bone marrow. RESULTS: GBM tumor-bearing mice treated with RT+NT-I7 increased T lymphocytes in the lymph nodes, thymus, and spleen, enhanced IFNγ production, and decreased Tregs in the tumor which was associated with a significant increase in survival. NT-I7 also enhanced central memory and effector memory CD8 T cells in lymphoid organs and tumor. Depleting CD8 T cells abrogated the effects of NT-I7. Furthermore, NT-I7 treatment decreased progenitor cells in the bone marrow. CONCLUSIONS: In orthotopic glioma-bearing mice, NT-I7 mitigates RT-related lymphopenia, increases cytotoxic CD8 T lymphocytes systemically and in the tumor, and improves survival. A phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).