Tele-neuro-oncology: Current Practices and Future Directions.

PURPOSE OF REVIEW: The purpose of this review is to describe the current state of telemedicine within neuro-oncology. This article will address the development of tele-neuro-oncology over time with a focus on current use and applications of telemedicine within the field. Current modalities and practical considerations for tele-neuro-oncology visits and opportunities for growth will be highlighted. RECENT FINDINGS: The use of telemedicine has expanded significantly during the COVID-19 pandemic, particularly within neuro-oncology. The use of telemedicine is widely accepted by neuro-oncologic patients and providers and continues to expand in utilization and scope. The use of tele-neuro-oncology is expected to develop further with opportunities for multidisciplinary and integrated care, clinical trials, research, and education. Telemedicine provides a unique, patient-centered approach to neuro-oncologic care. Telehealth will remain a valuable tool, and its use and role are expected to expand within neuro-oncology.

Clinical Trial Considerations in Neuro-oncology.

OPINION STATEMENT: Clinical trials play a critical role in discovering new treatments, but the path to regulatory approval can be cumbersome and time consuming. Efforts to increase the efficiency and interpretability of clinical trials within the neuro-oncology community have focused on standardization of response assessment, development of consensus guidelines for clinical trial conduct, decentralization of clinical trials, removal of barriers to clinical trial accrual, and re-examination of patient eligibility criteria.

The role of mRNA in the development, diagnosis, treatment and prognosis of neural tumors.

Neural tumors can generally be divided into central nervous system tumors and peripheral nervous tumors. Because this type of tumor is located in the nerve, even benign tumors are often difficult to remove by surgery. In addition, the majority of neural tumors are malignant, and it is particular the same for the central nervous system tumors. Even treated with the means such as chemotherapy and radiotherapy, they are also difficult to completely cure. In recent years, an increasingly number of studies have focused on the use of mRNA to treat tumors, representing an emerging gene therapy. The use of mRNA can use the expression of some functional proteins for the treatment of genetic disorders or tissue repair, and it can also be applied to immunotherapy through the expression of antigens, antibodies or receptors. Therefore, although these therapies are not fully-fledged enough, they have a broad research prospect. In addition, there are many ways to treat tumors using mRNA vaccines and exosomes carrying mRNA, which have drawn much attention. In this study, we reviewed the current research on the role of mRNA in the development, diagnosis, treatment and prognosis of neural tumors, and examine the future research prospects of mRNA in neural tumors and the opportunities and challenges that will arise in the future application of clinical treatment.

Downregulated NORAD in neuroblastoma promotes cell proliferation via chromosomal instability and predicts poor prognosis.

Increasing evidence suggests that long non-coding RNAs (lncRNAs) are involved in neuroblastoma (NB) pathogenesis. The aim of this study was to elucidate the roles and underlying mechanism of non-coding RNA activated by DNA damage (NORAD) in childhood NB. Both public data and clinical specimens were used to determine NORAD expression. Colony formation, cell proliferation and wound healing assays were performed to evaluate NORAD effects on proliferation and migration of SH-SY5Y and SK-N-BE(2) cells. Flow cytometry was used to examine the cell cycle changes. The expression of genes and proteins involved in chromosomal instability was determined by qRT-PCR and western blotting, respectively. Our results showed that low NORAD expression correlated with advanced tumor stage, high risk and MYCN amplification in both public data and clinical samples. Kaplan-Meier analysis indicated that patients with low NORAD expression had poor survival outcomes. Functional research showed that NORAD knockdown promoted cell proliferation and migration, and arrested the cell cycle at the G2/M phase. Moreover, the expression of the DNA damage sensor, PARP1, increased after NORAD knockdown, indicating a potential contribution of NORAD to DNA damage repair. NORAD silencing also affected the expression of genes and proteins related to sister chromatid cohesion and segregation, which are involved in chromosomal instability and consequent aneuploidy. These results suggest that NORAD may serve as a tumor suppressor in NB pathogenesis and progression. Thus, NORAD is a potential therapeutic target and a promising prognostic marker for NB patients.

The importance of local control management in high-risk neuroblastoma in South Africa.

PURPOSE: To investigate the impact of local therapies on high-risk neuroblastoma (HR-NB) outcomes in South Africa. METHODS: Data from 295 patients with HR-NB from nine pediatric oncology units between 2000 and 2014 were analysed. All patients received chemotherapy. Five-year overall (OS) and event free survival (EFS) were determined for patients who had received local therapy, either surgery or radiotherapy or both. RESULTS: Surgery was performed in only 35.9% (n = 106/295) patients. Surgical excision was done for 34.8% (n = 85/244) of abdominal primaries, 50.0% (n = 11/22) of thoracic primaries; 22.2% (n = 2/9) neck primaries and 66.7% (n = 8/12) of the paraspinal primaries. Only 15.9% (n = 47/295) of all patients received radiotherapy. Children, who had surgery, had an improved five-year OS of 32.1% versus 5.9% without surgery (p < 0.001). Completely resected disease had a five-year OS of 30.5%, incomplete resections 31.4% versus no surgery 6.0% (p < 0.001). Radiated patients had a five-year OS of 21.3% versus 14.2% without radiotherapy (p < 0.001). Patients who received radiotherapy without surgical interventions, had a marginally better five-year OS of 12.5% as opposed to 5.4% (p < 0.001). Patients who underwent surgery had a longer mean overall survival of 60.9 months, while patients, who were irradiated, had a longer mean overall survival of 7.9 months (p < 0.001). On multivariate analysis, complete metastatic remission (p < 0.001), surgical status (p = 0.027), and radiotherapy status (p = 0.040) were significant predictive factors in abdominal primaries. CONCLUSION: Surgery and radiotherapy significantly improve outcomes regardless of the primary tumor site, emphasizing the importance of local control in neuroblastoma.

Applied Precision Cancer Medicine in Neuro-Oncology.

Brain tumours that are refractory to treatment have a poor prognosis and constitute a major challenge in offering effective treatment strategies. By targeting molecular alterations, precision cancer medicine may be a viable option for the treatment of brain tumours. In this retrospective analysis of our PCM platform, we describe the molecular profiling of primary brain tumours from 50 patients. Tumour samples of the patients were examined by a 161-gene next-generation sequencing panel, immunohistochemistry, and fluorescence in situ hybridization (FISH). We identified 103 molecular aberrations in 36 (72%) of the 50 patients. The predominant mutations were TP53 (14.6%), IDH1 (9.7%) and PIK3CA (6.8%). No mutations were detected in 14 (28%) of the 50 patients. IHC demonstrated frequent overexpression of EGFR and mTOR, in 38 (76%) and 35 (70%) patients, respectively. Overexpression of PDGFRa and PDGFRb were less common and detected in 16 and four patients, respectively. For 35 patients a targeted therapy was recommended. In our database, the majority of patients displayed mutations, against which targeted therapy could be offered. Based on our observations, PCM may be a feasible novel treatment approach in neuro-oncology.

Inter- and Intraobserver Agreement of Canine and Feline Nervous System Tumors.

In routine diagnostic activity, pathologists may be confronted with nervous system tumors. The lack of clinical information, economic restrictions for additional testing, and the lack of expertise in neuropathology may render the diagnosis challenging. The goals of this study were to assess the agreement in diagnosing nervous system tumors in domestic carnivores among 4 board-certified surgical pathologists without particular expertise in neuropathology and a neuropathologist expert, and to investigate the utility of special stains frequently used in routine diagnostic laboratories. Forty-six tumors (7 cats, 38 dogs, and 1 unknown carnivore) were retrieved and 1 hematoxylin and eosin-stained slide per tumor was selected. Diagnoses (tumor type and subtype) were formulated based on histological features and available clinical information. Confidence in the diagnosis was also scored. Subsequently, a panel of histochemical and immunohistochemical stains (Gordon Sweet silver stain and immunohistochemistry for AE1/AE3, vimentin, glial fibrillary acid protein, S100, neuron-specific enolase and neurofilament) was evaluated by the pathologists, who either confirmed or changed their original diagnoses. Intraobserver and interobserver agreement and confidence in relation to diagnosis before and after analysis of special stains were assessed. The use of special stains increased the complete agreement among surgical pathologists, with regard to tumor type, from 63% to 74%. Cases with a high confidence score had a higher interobserver agreement than cases with a low confidence score. These results suggest that pathologists without expertise in neuropathology agree in the diagnosis of most nervous system tumors, and special stains available in most laboratories only slightly increase this agreement.

Targeting Long Non-Coding RNAs in Nervous System Cancers: New Insights in Prognosis, Diagnosis and Therapy.

Long non-coding RNAs (lncRNAs) constitute one of the most broad and diverse classes of cellular transcripts, playing key roles as regulatory molecules in many biological processes. Although the biology of lncRNAs is a new and emerging field of research, several studies have already shown that alterations in the expression of lncRNAs are associated with the development and progression of cancer in different organs and tissues, including central and peripheral nervous system. In this review, we summarize the oncogenic and tumor suppressive roles of lncRNAs in malignant tumors of the nervous system, such as glioma and neuroblastoma, focusing on their functional interactions with DNA, other RNA and protein molecules. We further discuss the potential use of lncRNAs as biomarkers for diagnosis, prognosis and tumor treatment. Gaining insight into the functional association between nervous system malignancies and lncRNAs could offer new perspectives to the development of promising therapeutic tools against cancer.

CD133 expression and MYCN amplification induce chemoresistance and reduce average survival time in pediatric neuroblastoma.

Objectives Neuroblastoma (NB) is the most common pediatric solid tumor derived from the sympathetic nervous system. MYCN is amplified in nearly half of patients with NB, and its association with rapid disease progression and poor outcome is controversial. Characterization of cancer stem cells (CSCs) in NBs has been rarely studied. This study was performed to determine whether MYCN and CD133+ CSCs are associated with chemotherapy resistance and the survival time of patients with NB. Methods Fifty patients with an unequivocal pathological diagnosis of NB were recruited. MYCN expression levels were measured before therapy. CSCs were derived and their multipotency tested by directed differentiation. The patients' responses to chemotherapy and average survival time were compared among the groups as follows: CD133+, CD133-, MYCN amplification ≥5 times (i.e. MYCN≥5), MYCN<5, CD133+ plus MYCN≥5, and CD133- plus MYCN<5. Results CD133+ CSCs differentiated into neuron-like cells. CD133+ patients had a significantly poorer response to chemotherapy than did CD133- patients. CD133+ plus MYCN≥5 patients had a significantly shorter average survival time than did CD133- plus MYCN<5 patients. Conclusions CD133+ CSCs are chemoresistance. CD133 expression and MYCN amplification can be used together as a prognostic indicator of disease outcome.

Management of Neuroblastoma: ICMR Consensus Document.

Neuroblastoma (NBL) is the most common extra-cranial solid tumor in childhood. High-risk NBL is considered challenging and has one of the least favourable outcomes amongst pediatric cancers. Primary tumor can arise anywhere along the sympathetic chain. Advanced disease at presentation is common. Diagnosis is established by tumor biopsy and elevated urinary catecholamines. Staging is performed using bone marrow and mIBG scan (FDG-PET/bone scan if mIBG unavailable or non-avid). Age, stage, histopathological grading, MYCN amplification and 11q aberration are important prognostic factors utilized in risk stratification. Low-risk disease including Stage 1 and asymptomatic Stage 2 disease has an excellent prognosis with non-mutilating surgery alone. Perinatal adrenal neuroblastoma may be managed with close observation alone. Intermediate-risk disease consisting largely of unresectable/symptomatic Stage 2/3 disease and infants with Stage 4 disease has good outcome with few cycles of chemotherapy followed by surgical resection. Paraspinal neuroblastomas with cord compression are treated emergently, typically with upfront chemotherapy. Asymptomatic Stage 4S disease may be followed closely without treatment. Organ dysfunction and age below 3 mo would warrant chemotherapy in 4S. High-risk disease includes older children with Stage 4 disease and MYCN amplified tumors. High-risk disease has a suboptimal outcome, though the survival is improving with multimodality therapy including autologous stem cell transplant and immunotherapy. Relapse after multimodality therapy is difficult to salvage. Late presentation, lack of transplant facility, malnutrition and treatment abandonment are additional hurdles for survival in India. The review provides a consensus document on management of NBL for developing countries, including India.

Clinical validation of urine 3-methoxytyramine as a biomarker of neuroblastoma and comparison with other catecholamine-related biomarkers.

Background Urinary dopamine, homovanillic acid and 4-hydroxy-3-methoxymandelic acid are established tests for diagnosis and monitoring of neuroblastic disease. We compared the diagnostic performance of total urinary 3-methoxytyramine, the O-methylated product of dopamine, to these three established tumour markers. Methods Urinary 3-methoxytyramine, dopamine, homovanillic acid and 4-hydroxy-3-methoxymandelic acid were measured by high-performance liquid chromatography with electrochemical detection on consecutive urine samples from histologically proven neuroblastic patients and controls. Patients with neuroblastic disease were further classified as untreated, advancing, residual or absent disease based on clinical and radiological criteria. Receiver operating characteristic curve analysis was used to compare the diagnostic performance of the four tumour markers. Results Urinary 3-methoxytyramine was well correlated with established tumour markers and its concentration correlated with disease activity. It was the most commonly elevated tumour marker in neuroblastic disease and showed similar sensitivity to dopamine and homovanillic acid. The diagnostic utility of urinary 3-methoxytyramine as measured by area under the receiver operating characteristic curve was similar to dopamine and homovanillic acid. Conclusion Our results support the use of urinary 3-methoxytyramine as a tumour marker in the diagnosis and the monitoring of neuroblastoma disease.

Risk of Second Primary Cancers in Multiple Myeloma Survivors in German and Swedish Cancer Registries.

We aimed at investigating the distribution and risk of second primary cancers (SPCs) in multiple myeloma (MM) survivors in Germany and Sweden to provide etiological understanding of SPCs and insight into their incidence rates and recording practices. MM patients diagnosed in 1997-2010 at age ≥15 years were selected from the Swedish (nationwide) and 12 German cancer registries. Standardized incidence ratios (SIRs) were used to assess risk of a specific SPC compared to risk of the same first cancer in the corresponding background population. Among 18,735 survivors of first MM in Germany and 7,560 in Sweden, overall 752 and 349 SPCs were recorded, respectively. Significantly elevated SIRs of specific SPCs were observed for acute myeloid leukemia (AML; SIR = 4.9) in Germany and for kidney cancer (2.3), AML (2.3) and nervous system cancer (1.9) in Sweden. Elevated risk for AML was more pronounced in the earlier diagnosis period compared to the later, i.e., 9.7 (4.2-19) for 1997-2003 period versus 3.5 (1.5-6.9) for 2004-2010 in Germany; 3.8 (1.4-8.3) for 1997-2003 versus 2.2 (0.3-7.8) for 2004-2010 in Sweden. We found elevated risk for AML for overall, early diagnosis periods and longer follow-up times in both populations, suggesting possible side effects of treatment for MM patients.

Pseudoneoplasms in the nervous system.

Pseudotumors are frequent in the nervous system and form a category of lesions that are fraught with peril for the pathologist unaware of the similarities and differences with neoplasms. The most common pseudoneoplasms in the nervous system are demyelinative, inflammatory and vascular. Even normal histology can be mistaken for neoplasm.

Immunotherapy response assessment in neuro-oncology: a report of the RANO working group.

Immunotherapy is a promising area of therapy in patients with neuro-oncological malignancies. However, early-phase studies show unique challenges associated with the assessment of radiological changes in response to immunotherapy reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumour regression, can still occur after initial disease progression or after the appearance of new lesions. Refinement of the response assessment criteria for patients with neuro-oncological malignancies undergoing immunotherapy is therefore warranted. Herein, a multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describe immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria based on guidance for the determination of tumour progression outlined by the immune-related response criteria and the RANO working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease within 6 months of initiating immunotherapy, including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for the use of corticosteroids. We review the role of advanced imaging techniques and the role of measurement of clinical benefit endpoints including neurological and immunological functions. The iRANO guidelines put forth in this Review will evolve successively to improve their usefulness as further experience from immunotherapy trials in neuro-oncology accumulate.

Symptomatic diagnosis of cancer of the brain and central nervous system in primary care: a systematic review.

BACKGROUND: We performed a systematic review of diagnostic studies of symptomatic patients in primary care to quantify the risk of brain/central nervous system (CNS) cancer in patients presenting in primary care with symptoms that may indicate brain/CNS cancer. OBJECTIVE: To quantify the risk of brain/CNS cancer in symptomatic patients presenting in primary care. METHODS: We searched Medline, Premedline, Embase, the Cochrane Library, Web of Science and ISI Proceedings (1980 to August 2014) and PsychInfo (1980 to February 2013) for diagnostic studies of symptomatic adult patients in primary care. Study quality was assessed using QUADAS-II and data were extracted to calculate the positive predictive values (PPVs) of symptoms, singly or in combination, for brain/CNS cancer. RESULTS: Six studies with 159938 patients were included. The PPVs of single symptoms were very low with only 'new-onset seizure' being above 1% in patients aged 18 years and above, rising to 2.3% in patients aged 60-69 years. In patients aged 15-24 years, the PPVs for the individual symptoms were also very low, with the highest, also for seizure, being 0.024%, similar to that in children aged 0-14 years of 0.02%. For symptom combinations, none of the PPVs were above 0.39%. CONCLUSIONS: All the symptoms of brain tumours are individually low risk, apart from new-onset epilepsy. This provides a real diagnostic problem, as brain tumours have all the expected features seen with cancer diagnostic delay, with high proportions presenting as an emergency and having had multiple primary care consultations before referral, and the prognosis is poor. Improving these metrics can only be done by liberalizing investigation, although the health economics of that strategy is undetermined.

Vagus nerve schwannoma in the parapharyngeal space: surgical, histological and immunohistochemical aspects. A case report.

Tumors of the parapharyngeal space are rare accounting approximately for 0.5% of all head and neck tumors. In the retrostyloid space, schwannomas are a more common finding, in contrast to other tumors. Usually, they present with a variety of slight symptoms until they grow in size and compress surrounding organs. Surgical treatment of parapharyngeal space tumors is difficult; due to the anatomical complex area, they develop in, and include several approaches, according to its size and relations. In this paper, we present a case of a 63-year-old female with a vagus nerve schwannoma in the parapharyngeal space. Beside the surgical difficulties, the resected tumor had a peculiar histopathological aspect (large areas of degeneration and atypia and little typical palisading) that compelled a thorough histological and immunohistochemical evaluation for positive and differential diagnosis.