sirolimus and Spinal-Neoplasms

The objective of this systematic review was to synthesize evidence regarding spinal screening recommendations, types of spinal and thoracic neurofibromatosis type 1 (NF1) tumors, medical therapy for NF1-associated neoplasms, and treatment with magnetically controlled growing rods (MCGRs) or cervical kyphosis correction in pediatric patients with NF1. We queried PubMed, Embase, Cochrane Library, Web of Science, Scopus, Clinicaltrials.gov, and medRxiv for studies reporting spinal screening recommendations, prognosis, and medical therapy for NF1-associated spinal tumors and MCGR use or cervical kyphosis correction in pediatric NF1 patients, yielding 758 publications, 33 of which were included. There is no consensus on spinal screening interval. Computed tomography is recommended for postoperative monitoring. Patients with gangliomas and spinal neurofibromas had nearly complete symptom resolution after resection. Plexiform neurofibromas were most commonly treated with resection and laminectomy; some patients reported tumor enlargement after intervention. Malignant nerve sheath tumors have high rates of metastasis even after chemoradiation and resection. MEK-inhibitors produced limited regression in tumor size. Sirolimus and thalidomide reduced tumor size but caused more severe adverse effects than MEK-inhibitors. Improvements in major curves and T1-T12 height gain were reported after MCGR intervention. Anteroposterior arthrodesis produced the greatest correction of dystrophic cervical kyphosis. There may be value in establishing standardized spinal screening protocols for pediatric NF1 patients. Surgical correction of NF1-associated spinal deformity is effective, though current medical therapies for spinal tumors have limited success. Areas for further investigation include determining appropriate screening intervals, choice of medical therapy for spinal tumors, and long-term outcomes of MCGRs. Level of Evidence: IV.

Topics: Child; Humans; Kyphosis; Mitogen-Activated Protein Kinase Kinases; Neurofibromatosis 1; Sirolimus; Spinal Neoplasms; Thalidomide

Plexiform neurofibromas (PNs) are benign peripheral nerve sheath tumors that arise in one-third of individuals with neurofibromatosis type 1 (NF1). They may cause significant disfigurement, compression of vital structures, neurologic dysfunction, and/or pain. Currently, the only effective management strategy is surgical resection. Converging evidence has demonstrated that the NF1 tumor suppressor protein, neurofibromin, negatively regulates activity in the mammalian Target of Rapamycin pathway.. We employed a 2-strata clinical trial design. Stratum 1 included subjects with inoperable, NF1-associated progressive PN and sought to determine whether sirolimus safely and tolerably increases time to progression (TTP). Volumetric MRI analysis conducted at regular intervals was used to determine TTP relative to baseline imaging.. The estimated median TTP of subjects receiving sirolimus was 15.4 months (95% CI: 14.3-23.7 mo), which was significantly longer than 11.9 months (P < .001), the median TTP of the placebo arm of a previous PN clinical trial with similar eligibility criteria.. This study demonstrated that sirolimus prolongs TTP by almost 4 months in patients with NF1-associated progressive PN. Although the improvement in TTP is modest, given the lack of significant or frequent toxicity and the availability of few other treatment options, the use of sirolimus to slow the growth of progressive PN could be considered in select patients.

Topics: Adolescent; Adult; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Male; Middle Aged; Neurofibroma, Plexiform; Neurofibromatosis 1; Sirolimus; Spinal Neoplasms; Treatment Outcome; Young Adult

Imatinib (IM) is active in advanced chordoma. The evidence of upstream and/or downstream mammalian target of rapamycin (mTOR) pathway activation prompted us to combine an mTOR inhibitor, sirolimus, to IM in IM-resistant advanced chordoma.. Since July 2007, 10 progressive advanced chordoma patients with secondary resistance to IM, and biochemical and/or immunohistochemical evidence of upstream and/or downstream mTOR effector activation, started IM (400 mg/day) plus sirolimus (2 mg/day) on a named basis.. The mean treatment duration was 9 months. Of nine patients assessable for response, at 3 months, we had one RECIST partial response (PR), seven stable disease (SD) and one progressive disease (PD). According to Choi criteria applied even to magnetic resonance imaging, we had seven PR (> or =10% decrease in size in four cases), one SD and one PD. Seven patients had a positron emission tomography response. The clinical benefit [RECIST complete response + PR + SD > or =6 months] was 89%. Pretreatment mTOR effectors analysis carried out in nine cases was positive in all patients (AKT activation in six patients, S6Sp6 expression/activation in seven). Post-treatment biopsy in one responsive patient confirmed S6 switch off.. In addition to PDGFRB, mTOR pathway can be activated in chordomas and the combination of IM plus rapalogs may be effective in IM-resistant chordomas.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Blotting, Western; Chordoma; Female; Humans; Imatinib Mesylate; Magnetic Resonance Imaging; Male; Middle Aged; Oncogene Protein v-akt; Piperazines; Pyrimidines; Sacrum; Sirolimus; Skull Base Neoplasms; Spinal Neoplasms; Treatment Outcome; Young Adult

Renal epithelioid angiomyolipomas (EAML) are rare tumors with aggressive behavior. EAML can be sporadic or develop within the tuberous sclerosis complex syndrome, where mutations of TSC1 or TSC2 genes (critical negative regulators of mTOR Complex 1) result in an increased activation of mTOR pathway. Optimal EAML treatment, including mTOR inhibitors, remains undetermined.. Here we present the case of a young adult with a renal EAML that after radical nephrectomy developed metastases, first in liver and then in lumbar vertebrae. After complete surgical resection of these lesions, liver recurrence was detected, this time with incomplete surgical resection. After finding a new liver lesion, systemic treatment with sirolimus started. The patient exhibited a complete and durable response to this drug, being disease free at the time of publication, after 36 months of treatment. Targeted next generation sequencing (NGS) of MTOR, TSC1 and TSC2 genes in the primary tumor, metastasis and blood of the patient, revealed one inactivating TSC2 mutation (c.2739dup; p.K914*) in the tumor cells. Immunohistochemistry revealed decreased TSC2 protein content and increased phospho-S6 in the tumor cells, demonstrating mTOR pathway activation.. NGS on an EAML patient with an extraordinary response to sirolimus uncovered TSC2 inactivation as the mechanism for the response. This study supports NGS as a useful tool to identify patients sensitive to mTOR inhibitors and supports the treatment of malignant EAML with these drugs.

Topics: Adult; Angiomyolipoma; Antibiotics, Antineoplastic; Chemotherapy, Adjuvant; Hepatectomy; Humans; Kidney Neoplasms; Liver Neoplasms; Male; Mutation; Nephrectomy; Signal Transduction; Sirolimus; Spinal Neoplasms; TOR Serine-Threonine Kinases; Treatment Outcome; Tuberous Sclerosis Complex 2 Protein