The NOMS approach to metastatic tumors: Integrating new technologies to improve outcomes / El enfoque de NOMS para los tumores metastásicos: integración de nuevas tecnologías para mejorar los resultados

Los paradigmas de tratamiento para pacientes con metástasis de columna vertebral han evolucionado significativamente en las últimas dos décadas. El cambio más transformador de estos paradigmas ha sido la integración de la radiocirugía estereotáctica espinal (sSRS). La sSRS permite la administración de dosis de radiación lítica con preservación de los órganos cercanos en riesgo, particularmente la médula espinal. La evidencia apoya la seguridad y la eficacia de la radiocirugía, ya que actualmente ofrece un control tumoral local duradero con bajas tasas de complicaciones, incluso para tumores que anteriormente se consideraban radiorresistentes a la radioterapia convencional de haz externo. El papel de la intervención quirúrgica sigue siendo consistente, pero se ha observado una tendencia hacia técnicas menos agresivas, a menudo mínimamente invasivas. Utilizando tecnologías modernas e instrumentación mejorada, los resultados quirúrgicos continúan mejorando con una morbilidad reducida. Además, los agentes dirigidos, como los productos biológicos y los inhibidores de puntos de control, han revolucionado la atención del cáncer al mejorar tanto el control local como la supervivencia del paciente. Estos avances han dado lugar a la necesidad de nuevas herramientas de pronóstico y a una revisión más crítica de los resultados a largo plazo. La naturaleza compleja de los esquemas de tratamiento actuales requiere un enfoque multidisciplinario que incluya cirujanos, oncólogos médicos, oncólogos radioterápicos, intervencionistas y especialistas en dolor. Esta revisión recapitula los datos actuales basados en la evidencia sobre el tratamiento de las metástasis espinales e integra estos datos en un marco de decisión, NOMS, que se basa en cuatro pilares centinela de la toma de decisiones en tumores metastásicos de la columna vertebral: estado neurológico, comportamiento oncológico del tumor, estabilidad mecánica, y carga sistémica de la enfermedad y comorbilidades médicas.(AU)

Spinal metastases are a common oncologic challenge as 20–40% of cancer patients are affected during the course of their illness and up to 20% of those will become symptomatic from spinal cord compression.1–5 The magnitude of this problem is expected to grow commensurate with the exponential rise in the use of targeted therapies which have demonstrated markedly improved survivals for virtually all malignant tumors. Additionally, the increased availability of advanced diagnostic imaging such as magnetic resonance imaging and 18-FDG PET scans will also serve to increase detection of spine metastatic disease. Despite extended survivals conveyed by biologics and checkpoint inhibitors, the treatment goals for patients with spine metastases remain palliative and focused on the preservation or restoration of neurological function and spinal stability, improved pain control and health related quality of life (HRQOL), and durable tumor control. Scoring systems such as the Tomita score6 and Tokuhashi revised score7 historically have been used to estimate survival and dictate treatment but increasingly have become obsolete due to their inability to incorporate and account for advances in all domains of cancer treatment.(AU)

El enfoque de NOMS para los tumores metastásicos: integración de nuevas tecnologías para mejorar los resultados / The NOMS approach to metastatic tumors: Integrating new technologies to improve outcomes

Los paradigmas de tratamiento para pacientes con metástasis de columna vertebral han evolucionado significativamente en las últimas dos décadas. El cambio más transformador de estos paradigmas ha sido la integración de la radiocirugía estereotáctica espinal (sSRS). La sSRS permite la administración de dosis de radiación lítica con preservación de los órganos cercanos en riesgo, particularmente la médula espinal. La evidencia apoya la seguridad y la eficacia de la radiocirugía, ya que actualmente ofrece un control tumoral local duradero con bajas tasas de complicaciones, incluso para tumores que anteriormente se consideraban radiorresistentes a la radioterapia convencional de haz externo. El papel de la intervención quirúrgica sigue siendo consistente, pero se ha observado una tendencia hacia técnicas menos agresivas, a menudo mínimamente invasivas. Utilizando tecnologías modernas e instrumentación mejorada, los resultados quirúrgicos continúan mejorando con una morbilidad reducida. Además, los agentes dirigidos, como los productos biológicos y los inhibidores de puntos de control, han revolucionado la atención del cáncer al mejorar tanto el control local como la supervivencia del paciente. Estos avances han dado lugar a la necesidad de nuevas herramientas de pronóstico y a una revisión más crítica de los resultados a largo plazo. La naturaleza compleja de los esquemas de tratamiento actuales requiere un enfoque multidisciplinario que incluya cirujanos, oncólogos médicos, oncólogos radioterápicos, intervencionistas y especialistas en dolor. Esta revisión recapitula los datos actuales basados en la evidencia sobre el tratamiento de las metástasis espinales e integra estos datos en un marco de decisión, NOMS, que se basa en cuatro pilares centinela de la toma de decisiones en tumores metastásicos de la columna vertebral: estado neurológico, comportamiento oncológico del tumor, estabilidad mecánica, y carga sistémica de la enfermedad y comorbilidades médicas.(AU)

Spinal metastases are a common oncologic challenge as 20–40% of cancer patients are affected during the course of their illness and up to 20% of those will become symptomatic from spinal cord compression.1–5 The magnitude of this problem is expected to grow commensurate with the exponential rise in the use of targeted therapies which have demonstrated markedly improved survivals for virtually all malignant tumors. Additionally, the increased availability of advanced diagnostic imaging such as magnetic resonance imaging and 18-FDG PET scans will also serve to increase detection of spine metastatic disease. Despite extended survivals conveyed by biologics and checkpoint inhibitors, the treatment goals for patients with spine metastases remain palliative and focused on the preservation or restoration of neurological function and spinal stability, improved pain control and health related quality of life (HRQOL), and durable tumor control. Scoring systems such as the Tomita score6 and Tokuhashi revised score7 historically have been used to estimate survival and dictate treatment but increasingly have become obsolete due to their inability to incorporate and account for advances in all domains of cancer treatment.(AU)

[A Case of Spinal Cord Metastasis from Breast Cancer Successfully Treated with Trastuzumab Deruxtecan].

OBJECTIVE: Intramedullary spinal cord metastases(ISCM)are very rare in patients with breast cancer and have a poor prognosis with no established treatment. We report a case of ISCM in a patient with HER2-positive breast cancer who was successfully treated with a novel anti-HER2 agent, trastuzumab deruxtecan(T-DXd, ENHERTU®). CASE: The patient was a 44- year-old woman who underwent surgery for right breast cancer. T-DXd was introduced as the fourth-line metastatic treatment for multiple metastases, including liver, bone, pituitary, brain, and spinal cord metastases. Hematologic and non- hematologic toxicities did not occur during the treatment with T-DXd. T-DXd could be administered continuously for 25 cycles, and symptoms such as numbness in the left lower limb were controlled without progression of the brain and spinal cord, although T-DXd-induced interstitial lung disease was a concern. DISCUSSION: ISCM is a rare metastatic lesion that is difficult to treat with chemotherapy due to the blood-brain barrier (BBB), and there is no established treatment for ISCM. T-DXd has shown promising results in previous clinical trials, including in patients with central nerve system (CNS) metastases, and is expected to be a good treatment option for CNS metastases in clinical practice. CONCLUSION: This successful case of T-DXd for ISCM suggests that T-DXd is an effective treatment option for patients with breast cancer and CNS metastases.

Biodegradable controlled-release polymer containing butylidenephthalide to treat a recurrent cervical spine glioblastoma with promising result: a compassionate trial report.

Intramedullary spinal glioblastoma multiforme (GBM) tends to recur within 11 months of surgical resection, even after adjuvant chemoradiation therapy. Treatment options for recurrent spinal GBM are often limited. (Z)-n-butylidenephthalide [(Z)-BP] is a natural compound that induces apoptosis, antiproliferation, anti-invasion and antistemness effects in GBM cells. The Cerebraca wafer consists of (Z)-BP within a biodegradable wafer that can be implanted in the parenchyma of the central nervous system to treat high-grade glioma. We present a 44-year-old woman with a recurrent spinal GBM who underwent microscopic surgical tumor excision under fluorescein sodium guidance and intraoperative neurophysiologic monitoring. Four Cerebraca wafers were implanted into the cord and intradural space during the operation. MRI revealed that both tumor volume and spinal cord edema had decreased 4 days after surgery; both had substantially decreased 16 months after surgery. Neurologic functions and quality of life were improved after salvage therapy. No adverse events were reported. Cerebraca wafer implantation during surgical re-excision of spinal GBM may be a novel therapeutic approach for reduction of the tumor size and subsequent spinal cord edema with no toxicity to the spinal cord.

Diffuse leptomeningeal glioneuronal tumour (DLGNT) in children: the emerging role of genomic analysis.

Diffuse leptomeningeal glioneuronal tumours (DLGNT) represent rare enigmatic CNS tumours of childhood. Most patients with this disease share common radiological and histopathological features but the clinical course of this disease is variable. A radiological hallmark of this disease is widespread leptomeningeal enhancement that may involve the entire neuroaxis with predilection for the posterior fossa and spine. The classic pathologic features include low- to moderate-density cellular lesions with OLIG2 expression and evidence of 'oligodendroglioma-like' appearance. The MAPK/ERK signaling pathway has recently been reported as a potential driver of tumourigenesis in up to 80% of DLGNT with KIAA1549:BRAF fusions being the most common event seen. Until now, limited analysis of the biological drivers of tumourigenesis has been undertaken via targeted profiling, chromosomal analysis and immunohistochemistry. Our study represents the first examples of comprehensive genomic sequencing in DLGNT and shows that it is not only feasible but crucial to our understanding of this rare disease. Moreover, we demonstrate that DLGNT may be more genomically complex than single-event MAPK/ERK signaling pathway tumours.

Bevacizumab as a surgery-sparing agent for spinal ependymoma in patients with neurofibromatosis type II: Systematic review and case.

Neurofibromatosis type 2 (NF2) is a rare, hereditary tumor syndrome, often requiring repeated surgeries for multiple lesions with significant cumulative morbidity. As such, non-operative management should be considered when possible for this patient population. The aim of this study is to provide a systematic review of the literature regarding this treatment strategy. A descriptive case of a patient in whom bevacizumab treatments enabled over 15 years of surgical postponement for a symptomatic spinal cord ependymoma is also provided. Evidence suggests that bevacizumab is a reasonable surgery-deferring option for cystic lesions, and it may be especially useful in NF2 patients to reduce cumulative morbidity.

Response to BRAF and MEK1/2 inhibition in a young adult with BRAF V600E mutant epithelioid glioblastoma multiforme: A Case Report and Literature Review.

Epithelioid glioblastoma multiforme (eGBM) is a rare and aggressive variant of glioblastoma multiforme (GBM) that predominantly affects younger patients and can be difficult to distinguish from other gliomas. Data on how patients with eGBM might be best treated are limited, although genomic analyses have shown that almost half of tumours harbour activating BRAF gene mutations. Here we present the case of a young female with BRAF V600E-mutant eGBM who had a prolonged response to targeted therapy with the BRAF and MEK1/2 inhibitors dabrafenib and trametinib. We review current knowledge about eGBM, including the emerging role for BRAF- ± MEK1/2- targeted therapy.

Response to combined BRAF/MEK inhibition in adult BRAF V600E mutant spinal pilocytic astrocytoma.

Pilocytic astrocytomas are World Health Organisation (WHO) grade I tumors, occurring predominantly supratentorially and in the pediatric population. Although the mainstay of treatment is local therapies such as surgery, targeted systemic therapies may be necessary for recurrent or unresectable disease. The majority of sporadic pilocytic astrocytomas are associated with the BRAF-KIAA fusion gene, which results in constitutive activation of the MAP Kinase pathway. Less frequently, the BRAF V600E point mutation has been described, occurring in less than 10% of supratentorial pilocytic astrocytomas. Tumours with this mutation may respond to targeted therapy against the BRAF/MAP Kinase pathway. We report the first described case of a spinal pilocytic astrocytoma in an adult patient with a BRAF V600E mutation responding to targeted therapy using BRAF and MEK tyrosine kinase inhibitors, and share our experiences with the management of toxicity in this patient population.

Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma.

PURPOSE OF REVIEW: H3K27M is a frequent histone mutation within diffuse midline gliomas and is associated with a dismal prognosis, so much so that the 2016 CNS WHO classification system created a specific category of "Diffuse Midline Glioma, H3K27M-mutant". Here we outline the latest pre-clinical data and ongoing current clinical trials that target H3K27M, as well as explore diagnosis and treatment monitoring by serial liquid biopsy. RECENT FINDINGS: Multiple epigenetic compounds have demonstrated efficacy and on-target effects in pre-clinical models. The imipridone ONC201 and the IDO1 inhibitor indoximod have demonstrated early clinical activity against H3K27M-mutant gliomas. Liquid biopsy of cerebrospinal fluid has shown promise for clinical use in H3K27M-mutant tumors for diagnosis and monitoring treatment response. While H3K27M has elicited a widespread platform of pre-clinical therapies with promise, much progress still needs to be made to improve outcomes for diffuse midline glioma patients. We present current treatment and monitoring techniques as well as novel approaches in identifying and targeting H3K27M-mutant gliomas.

National trends in management of adult myxopapillary ependymomas.

Myxopapillary ependymomas (MPE) are WHO Grade I ependymomas that annually occur in 0.05-0.08 per 100,000 people. Surgical resection is the recommended first line therapy. Due to the rarity of the disease, there is a relatively poor understanding of the use of radiotherapy (RT) in managing this disease. The National Cancer Database (NCDB) was analyzed for patterns of care foradult MPE diagnosed between 2002 and 2016. Of 753 qualifying cases, the majority of patients underwent resection (n = 617, 81.9%). A relatively small portion received RT (n = 103, 13.3%) with most receiving RT post-operatively (n = 98, 95.1%). The likelihood of patients to undergo resection and RT was associated with patient age at diagnosis (p = 0.002), tumor size (p < 0.001), and race (p = 0.017). Chemotherapy was not widely utilized (0.27% of patients). One limitation of our analysis is that there was no data on progression free survival (PFS), an important outcome given the high survival rate in this disease. Surgery remains the primary means to manage adult MPE. For spinal MPE, it is understood that gross total resection (GTR) should be attempted whenever possible as GTR has been associated with improved PFS in several studies. The impact of RT on overall survival (OS) is indeterminate given the 1.6% death rate in the cohort. Analyses of the impact of RT on PFS in a larger database would be beneficial for determining an algorithm for post-operative and definitive RT in this disease entity.

Successful osimertinib treatment in a patient who exhibited intramedullary spinal cord metastases of lung adenocarcinoma with an acquired EGFR T790M mutation.

Intramedullary spinal cord metastases (ISCMs) of non-small cell lung cancer (NSCLC) constitute a serious if infrequent complication, characterised by rapid progression of neurological deficits, with poor prognosis. We describe a 52-year-old man with ISCMs secondary to lung adenocarcinoma who acquired the T790M mutation of the epidermal growth factor receptor (EGFR) after previous use of a first-generation EGFR tyrosine kinase inhibitor (TKI); he was successfully treated with osimertinib. This is the first report of the use of osimertinib in ISCMs: due to its high central nervous system activity, osimertinib could be useful for treating ISCMs secondary to NSCLC in patients who exhibit the T790M mutation.

Spinal Cord Toxicity from Intrathecal Chemotherapy: A Case with Clinicopathologic Correlation.

BACKGROUND: Myelopathy of the dorsal columns is a rare complication of intrathecal (IT) chemotherapy that occurs most frequently with IT methotrexate and cytarabine. This diagnosis is made with a combination of magnetic resonance imaging, somatosensory evoked potentials, and elevated cerebrospinal fluid (CSF) protein levels, particularly myelin basic protein. CASE DESCRIPTION: A 73-year-old man with blastic plasmacytoid dendritic cell neoplasm and known central nervous system involvement underwent standard treatment, including 5 doses of IT cytosine arabinoside. Following this, he had documented CSF clearance of disease. One year later, he developed progressive lower extremity weakness, numbness, and bowel/bladder dysfunction. Magnetic resonance imaging and repeat CSF analysis demonstrated recurrence, and he underwent further IT administration of methotrexate and cytarabine. CSF clearance of malignant cells was again established. However, weakness progressed to quadriplegia; loss of bowel/bladder control; and severe sensory loss, particularly vibration and proprioception. Repeat magnetic resonance imaging demonstrated high signal intensity in bilateral posterior columns. A lower thoracic spine dorsal column biopsy revealed cord destruction and diffuse macrophage infiltration with profound destruction of the neuropil. CONCLUSIONS: Although dorsal column myelopathy has previously been described in association with IT chemotherapy, this has solely been diagnosed on the basis of clinical examination, electrodiagnostic criteria, radiographic findings, and CSF analysis. This case provides a pathologic evaluation of an antemortem obtained specimen revealing diffuse macrophage infiltration and profound destruction of the neuropil. Whereas the mechanism underlying spinal cord toxicity following IT chemotherapy remains largely unknown, this case demonstrates a potentially macrophage-mediated process.

Intracranial remission with brigatinib rechallenge as fifth-line ALK inhibition therapy in a lung cancer patient.

Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors have been developed for the treatment of EML4-ALK-rearranged non-small-cell lung cancer, with the newer generation agents brigatinib, alectinib and lorlatinib showing pronounced central nervous system activities. Intracranial efficacy is an important feature for these agents, as metastatic lesions frequently occur in the central nervous system in the ALK-positive setting. Here, we report on an updated case of a patient who received her diagnosis in 2005 and has had disease progression with new lesions on six occasions over the last 8 years. During the first two progressions, only local recurrence was observed. After that, the lungs stayed clear and the patient progressed exclusively in the brain and spinal cord. Initial treatments consisted of chemotherapy and radiotherapy. In 2012, ALK-directed targeted therapy became available, and crizotinib was administered. The treatment was switched to brigatinib 3 years later because of spinal cord lesions. Brigatinib induced partial remission and was followed by lorlatinib and, later on, alectinib, when new metastases arose in the spinal cord and brain. Each of these drugs promoted complete remission of the recent lesions. In November 2018, imaging showed multiple cerebral metastases. As radiotherapy was not an option because of previous irradiation, and as chemotherapy cannot be expected to be active in the brain, the patient underwent brigatinib rechallenge, which led to partial remission. All of the central nervous system relapses were symptomatic, with symptoms resolved rapidly during treatment. This case of a patient with EML4-ALK-rearranged non-small-cell lung cancer shows that sequential treatment with next-generation ALK tyrosine kinase inhibitors, including rechallenge, can induce profound remission even in heavily pretreated patients, especially if the central nervous system is the site of progression.

False localizing sign caused by schwannoma in cervical spinal canal at C1-2 level: A case report.

RATIONALE: False localizing sign means that the lesion, which is the cause of the symptom, is remote or distant from the anatomical site predicted by neurological examination. This concept contradicts the classical clinicoanatomical correlation paradigm underlying neurological examinations. PATIENT CONCERNS: A 54-year-old man consulted for the right sciatica-like leg pain that had aggravated 1 year ago. Radiological examinations revealed degenerative spondylolisthesis with instability and right-sided recess stenosis at the L4-5 level. After initial improvement following 3 transforaminal epidural steroid injections with gabapentin and antidepressant medication, there was a recurrence of the symptoms a year later, along with wasting of the right leg for several months. Physical examination revealed difficulty in heel-walking and a weakness of extension of the right big toe; tendon reflexes were normal. Lumbar spine radiographs revealed no new findings. The initial course of treatment was repeated, but was ineffective. DIAGNOSES: Further cervicothoracic spine evaluations revealed a right-sided intradural-extramedullary mass and myelopathy at the C1-2 level. INTERVENTIONS: The cervical mass was surgically resected and identified histopathologically as a schwannoma. OUTCOMES: Immediately after surgery, sciatica-like pain and weakness of right leg were completely resolved. LESSONS: It is difficult to make an accurate diagnosis if there are symptoms caused by false localizing sign. Additionally, it is even more difficult to diagnose false localizing sign accurately when there is a co-existing lumbar lesion that can cause the similar symptoms.

Magnetic Drug Targeting: A Novel Treatment for Intramedullary Spinal Cord Tumors.

Most applications of nanotechnology in cancer have focused on systemic delivery of cytotoxic drugs. Systemic delivery relies on accumulation of nanoparticles in a target tissue through enhanced permeability of leaky vasculature and retention effect of poor lymphatic drainage to increase the therapeutic index. Systemic delivery is limited, however, by toxicity and difficulty crossing natural obstructions, like the blood spine barrier. Magnetic drug targeting (MDT) is a new technique to reach tumors of the central nervous system. Here, we describe a novel therapeutic approach for high-grade intramedullary spinal cord tumors using magnetic nanoparticles (MNP). Using biocompatible compounds to form a superparamagnetic carrier and magnetism as a physical stimulus, MNP-conjugated with doxorubicin were successfully localized to a xenografted tumor in a rat model. This study demonstrates proof-of-concept that MDT may provide a novel technique for effective, concentrated delivery of chemotherapeutic agents to intramedullary spinal cord tumors without the toxicity of systemic administration.

Primary B-cell Spinal Cord Lymphoma of the Cervical Spine.

Non-Hodgkin lymphomas are a heterogeneous group of tumours, with diffuse large B-cell lymphomas (DLBCL) being particularly common. Cases of DLBCLs developing in the central nervous system, especially in the spinal cord, are extremely rare and thus pose significant diagnostic and therapeutic problems, particularly for orthopaedists and neurologists since these are the specialists the patients first consult. The tumours often appear in immunosuppressed patients and standard chemotherapy is ineffective. This paper presents the case of a 44-year-old male with a lymphoma located in the spinal cord at the C7-Th1 level. The symptoms appeared suddenly and progressed rapidly, with dissociated sensory loss and limb paresis being the most pronounced. Imaging studies and the rapid symptom progression suggested neoplastic disease. An emergency surgical procedure was performed in order to decompress the spinal cord and thus limit neurological deficits. Tumour resection allowed for making a diagnosis. By four weeks after the surgery, the tumour had grown larger than before the procedure. Chemotherapy with MTX and Ara-C and intrathecal MTX resulted in full remission. Consolidation was achieved with radiotherapy. Currently, with the low incidence of such tumours, there are no standards of management in patients with DLBCLs of the CNS. The literature contains only a few case reports on successfully treated spinal cord DLBCLs.

ALK-rearranged lung cancer with intradural extramedullary spinal cord metastases responding to ceritinib treatment: A case report.

Intradural extramedullary spinal cord metastases in lung cancer are rarely reported, but are a disastrous event because of severe clinical symptoms and poor prognosis. Herein, we report a case of a lung cancer patient with ALK rearrangement who experienced brain, leptomeningeal, and intradural extramedullary spinal cord metastases after developing resistance to crizotinib. After ceritinib therapy, his clinical symptoms improved and magnetic resonance imaging revealed that the intradural extramedullary lesions had reduced.

Pseudoprogression successfully treated with bevacizumab in a child with spinal pilocytic astrocytoma.

CLINICAL CASE: We report on a 7-year-old female with spinal pilocytic astrocytoma complicated by pseudoprogression 1 month after completion of radiation therapy. Although she was initially treated with high-dose steroids, her clinical symptoms did not completely resolve, and magnetic resonance imaging (MRI) revealed extension of the lesions into the medulla oblongata. Treatment with bevacizumab was commenced, followed by rapid resolution of the clinical symptoms and improvements in the MRI findings. CONCLUSION: This case highlights the efficacy and tolerability of bevacizumab for the treatment of pseudoprogression in children with spinal low-grade gliomas.