Andreas Hottinger - Academia.edu (original) (raw)

Papers by Andreas Hottinger

Annals of Oncology, 2017

immune checkpoint inhibitors is PD-L1 expression status and this can change over time with the ef... more immune checkpoint inhibitors is PD-L1 expression status and this can change over time with the effect of therapies like chemotherapy and radiotherapy. The aim of this study is to determine whether PD-L1 expression status changes in recurrent gliomas after chemoradiotherapy and the impact of this change on survival. Methods: PD-L1 expression of 29 patients was evaluated by an expert pathologist with immunohistochemistry. PD-L1 positivity was defined as expression in 1% of tumor cells. Change in PD-L1 expression status was defined as an absolute 5% difference between two resections. Results: Of the 29 patients, 15 patients (51.7%) had PD-L1 expression in 1% of tumor cells and 7 patients (24.1%) had PD-L1 expression in 10% of tumor cells at diagnosis. Median survival of patients with baseline PD-L1 <%10 was 26 months, and in patients with PD-L1 %10 was 18 mo (P ¼ 0.063). The PD-L1 status did not change in 17 patients (58.6%). 8 patients had PD-L1 negative tumors both at diagnosis and at recurrence, while 9 patients had PD-L1 positive tumors both at diagnosis and at recurrence. In 6 patients (20.7%) a negative-to-positive switch and in 6 patients (20.7%) a positive to negative switch were seen. The change in PD-L1 status over time was not statistically significant. The change of PD-L1 over time did not influenced overall survival of the patients (P ¼ 0.45). Conclusions: The PD-L1expression status changes in more than 40% of high grade glial tumors at recurrence after receiving chemotherapy and radiotherapy. So immune responsiveness of glial tumors can be modified by treatments. As the patients in this study did not receive immunotherapy after recurrence, the change in PD-L1 expression probably did not affect survival.

New England Journal of Medicine

Neurology

Background and Objectives Patients with a new diagnosis of cancer carry an increased risk of acut... more Background and Objectives Patients with a new diagnosis of cancer carry an increased risk of acute ischemic stroke (AIS), and this risk varies depending on age, cancer type, stage, and time from diagnosis. Whether patients with AIS with a new diagnosis of neoplasm represent a distinct subset from those with a previously known active malignancy remains unclear. We aimed to estimate the rate of stroke in patients with newly diagnosed cancer (NC) and previously known active cancer (KC) and to compare the demographic and clinical features, stroke mechanisms, and long-term outcomes between groups. Methods Using 2003–2021 data from the Acute STroke Registry and Analysis of Lausanne registry, we compared patients with KC with patients with NC (cancer identified during AIS hospitalization or within the following 12 months). Patients with inactive and no history of cancer were excluded. Outcomes were the modified Rankin scale (mRS) score at 3 months and mortality and recurrent stroke at 12 m...

Revue médicale suisse, May 18, 2022

Revue Médicale Suisse, 2017

La nouvelle classification OMS 2016 des tumeurs du système nerveux central amène un grand renouve... more La nouvelle classification OMS 2016 des tumeurs du système nerveux central amène un grand renouveau puisqu’elle prend maintenant en compte des données de biologie moléculaire et aboutit à un « diagnostic intégré ». Elle définit ainsi des groupes diagnostiques plus homogènes en termes de pronostic et de valeur prédictive à un traitement, notamment pour les gliomes. Après un rappel sur le concept de cette nouvelle classification, les notions de base sur la génétique moléculaire des gliomes et l’application pratique du diagnostic intégré, une analyse de l’impact de cette classification sur le diagnostic et le devenir des gliomes portés à l’Institut universitaire de pathologie du CHUV d’octobre 2015 à novembre 2016 est rapportée.

Objective: Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor... more Objective: Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor in adults and the diagnosis is devastating to patients and their families. Treatment includes many modalities such as surgery, radiation, chemotherapy and tumor treating fields (TTFields). The latter is[for full text, please go to the a.m. URL]

Journal of Clinical Oncology, 2006

1532 Background: Matrix metalloproteinases have been associated with angiogenesis, tumor infiltra... more 1532 Background: Matrix metalloproteinases have been associated with angiogenesis, tumor infiltration and metastases formation in systemic lymphoma. Disease status in PCNSL is determined by brain MRI; however it may be inconclusive and non-invasive tests to evaluate disease status would be useful. This study was designed to determine whether circulating levels of MMP-9 could be related to disease status in PCNSL. Methods: Circulating levels of MMP-9 were determined by ELISA and correlated with disease status assessed by MRI in a prospective longitudinal study. The disease status was classified as no evidence of disease (CR) versus active disease (AD). Results: We enrolled 18 PCNSL patients and obtained 93 blood samples (median 6 per patient, range 1–10) from August 2002 to December 2005. When in CR (12 patients, 59 samples), the mean MMP-9 level was 205.5 ± 19.1 ng/ml (median 162.3 ng/ml, range: 35.9–649.1 ng/ml). MMP-9 levels were significantly higher in AD (16 patients, 34 samples...

Journal of Clinical Oncology, 2016

TPS2083Background: Therapeutic options are limited for refractory/relapsed adult medulloblastoma ... more TPS2083Background: Therapeutic options are limited for refractory/relapsed adult medulloblastoma with activation of sonic hedgehog pathway (SHH-MB). Inhibition of this pathway may offer an attracti...

Journal for ImmunoTherapy of Cancer, 2019

Background: Immune checkpoint inhibitors (ICPis) have revolutionised the treatment of melanoma by... more Background: Immune checkpoint inhibitors (ICPis) have revolutionised the treatment of melanoma by significantly increasing survival rates and disease control. However, ICPis can have specific immune-related adverse events, including rare but severe neurological toxicity. Case presentation: We report a 44-year-old man diagnosed with stage IIIB melanoma who developed metastatic disease (pulmonary and brain metastases) and was treated with stereotactic radiosurgery and nivolumab immunotherapy. He developed asymptomatic multifocal diffuse white matter lesions consistent with active central nervous system demyelination seen on brain MRI. One month after cessation of the immunotherapy, spontaneous regression of the demyelinating lesions was observed, suggesting a nivolumab-related toxicity. Conclusion: We report the first case of a melanoma patient with an asymptomatic and spontaneously reversible central nervous system demyelination following nivolumab immunotherapy. This case highlights the need for better recognition of such atypical and rare neurological toxicities which could be mistaken for progressive brain metastases. Early recognition and appropriate management are crucial to reduce severity and duration of these toxicities, especially for patients with less favourable evolution.

Clinical Neurology and Neurosurgery, 2019

The management of women with brain tumors in the early post-partum period may be demanding as the... more The management of women with brain tumors in the early post-partum period may be demanding as the pathophysiological changes that occur during pregnancy may also manifest in the early post-partum period. The aim of our paper is to report a case of late-onset post-partum pre-eclampsia after brain tumor surgery, complicated by posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS). Hemicraniectomy and intensive care management were necessary to obtain a favorable neurological outcome. The inherent literature on the subject is also analyzed through a systematic research. This is the first case of supratentorial decompressive hemicraniectomy in post-partum PRES, while there has been only one other case of posterior fossa decompression described in this cohort of patients. PRES and RCVS can complicate the neurosurgical management of women in the postpartum period. A careful evaluation of the clinical presentation is necessary as in some particular cases an aggressive medical and surgical treatment is required to obtain a favorable outcome.

Clinical Research (Excluding Clinical Trials), 2019

Introduction: Tumor Treating Fields (TTFields) are alternating electric fields delivered via tran... more Introduction: Tumor Treating Fields (TTFields) are alternating electric fields delivered via transducer arrays placed on the scalp The EF-14 [NCT00916409] trial showed improved survival outcomes in newly diagnosed Glioblastoma (GBM) patients treated with TTFields plus Temozolomide (TMZ) versus TMZ alone We analysed EF-14 data to test the hypothesis that because TTFields delivery is planned to optimize dose at the tumor bed: TTFields treated patients are more likely to exhibit distal progressions, including progression to the infratentorium, the region where TTFields dose is minimal when planning treatment to target primary tumors in the supratentorium Tumor growth rates are slower in patients treated with TMZ+TTFields Methods: Patients on treatment for more than two months who exhibited radiological progression were included in the study (treatment: N=280/466, control: N=122/229) Regions of enhancing tumor, necrosis and resection were contoured on T1 contrast MRIs taken at baseline and at the date of first progression reported by the treating center Progressions were classified into three groups: Local progressions: 3 mm from the original tumor or resection cavity; Combined local and distal progressions: both local and distal progressions were visible The growth rate of the tumor was estimated and the distance between the original lesions and new distal lesions was measured Patients with (distal) infratentorial progression were identified. Results: More cases of non local (distal or combined local and distal) progression were observed in the treatment arm The difference between the groups was not statistically significant (69/280 vs 23/122 P Conclusions: This imaging analysis of the EF-14 Phase III trial demonstrates that adding TTFields to TMZ has substantial impact on GBM growth patterns and rate In addition to prolongation of survival times during TTFields treatment, this is another validation for the local efficacy of TTFields therapy TTFields increases local control of tumor growth, emphasizing the need for adaptive treatment after progression to control progressing disease Further studies are needed to elucidate the association between progression and TTFields dose distributions. Citation Format: Suriya Jeyapalan, Steven A. Toms, Andreas Hottinger, Lawrence Kleinberg, Erqi Pollom, Scott G. Soltys, Martin Glas. Tumor Treating Fields alters progression patterns in glioblastoma: An imaging analysis of the EF-14 Phase III trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT205.

Journal of Clinical Oncology, 2016

e14123Background: Bromodomains (BRD) bind to acetylated lysine residues on histone tails and are ... more e14123Background: Bromodomains (BRD) bind to acetylated lysine residues on histone tails and are directly involved in remodeling chromatin and regulating transcription, thus representing a potentially important anticancer target. MK-8628 is a synthetic small molecule targeting BRD2, 3 and 4 of the tandem-BRD-containing family of transcriptional regulators, the BET proteins. It has shown cytotoxic activity in in vitro GB models. We conducted a phase IIa trial with dose optimization to determine the MTD, safety and clinical activity of MK-8628 in pts with a first GB recurrence. Methods: In the first step, a traditional 3+3 dose escalation schema was used. At first recurrence of GB, pts were treated with MK-8628 administered orally at 3 dose levels (DL1: 80 mg QD, DL2: 120 mg QD, DL3: 160 mg QD) with 4-week cycles. PK analyses were performed on day 1 of cycle 1 and residual samples were drawn on day 28. MRI assessment was performed every 2 cycles (RANO). Results: Twelve pts were included between December 201...

Current Opinion in Neurology, 2019

Purpose of review Immune checkpoint inhibitors (ICPI) and chimeric antigen receptor T cells (CAR-... more Purpose of review Immune checkpoint inhibitors (ICPI) and chimeric antigen receptor T cells (CAR-T) represent novel therapies recently approved to treat a number of human cancers. As both approaches modulate the immune system, they can generate a number of immune-related adverse events (irAEs), including a large spectrum of novel neurological toxicities. These are of special interest given their potential severity and risk of compromising further oncologic treatment. We aim to provide a comprehensive review of the literature and discuss their optimal management. Recent findings In contrast to irAEs involving other organs, neurological complications of ICPI are uncommon, may present throughout the course of treatment and involve the peripheral and central nervous system, including polyneuropathy, myositis, myasthenia gravis, demyelinating polyradiculopathy, myelitis, encephalitis and others. If started early, ICPI-related neurologic irAEs are usually responsive to steroids. In contra...

Neuro-Oncology, 2016

BACKGROUND: Tumor Treating Fields (TTFields) is an established, frequency-tuned, anti-mitotic, ph... more BACKGROUND: Tumor Treating Fields (TTFields) is an established, frequency-tuned, anti-mitotic, physical treatment modality that acts in metaphase, anaphase and telophase. TTFields are delivered to the brain by a patient operated, portable medical device (Optune™, Novocure Ltd.). An international, multicenter, prospective, randomized phase 3 trial (EF-14) was initiated in 2009 to test the efficacy and safety of combining TTFields with temozlomide (TMZ) compared to TMZ alone following radiation therapy with adjuvant TMZ in patients with newly diagnosed GBM. Results of a protocol pre-specified successful interim analysis on the first 315 patients randomized has been reported (Stupp et al. JAMA 2015). Here we report the main outcomes of all 695 patients enrolled with a mature minimum follow-up of 18 month (median follow-up 36 months) for all patients (Range 19–80 months).

Current Opinion in Neurology, 2016

Neurooncology is a fascinating field that requires very different capacities: its first mission i... more Neurooncology is a fascinating field that requires very different capacities: its first mission is to insure the management and diagnosis of primary central nervous system tumors as well as metastases of systemic cancers of the brain and spinal cord. The management of those tumors is highly complicated and requires the input and knowledge from experts of multiple medical specialties including neurology, oncology, neurosurgery, radiation oncology, neuroradiology and neuropathology. Because of this, a truly multidisciplinary team that is able to consider all aspects of the management of the patient is essential. Every single one of these specialties has seen an important progress in recent years. This is nicely illustrated in the present issue with two specific topics. Leptomeningeal dissemination is a common but often poorly understood complication of systemic cancer. It deserves a complete review of the current state of the art of its management. Finally, 2016 has been marked by a series of key publications of randomized trials for low-grade gliomas. These findings and how they might change daily practice are summarized in this issue. On the other hand, the second mission of neurooncology is the identification and management of

Brain and Spine Surgery in the Elderly, 2017

Primary central nervous system lymphoma (PCNSL) describes a malignant extranodal non-Hodgkin’s ly... more Primary central nervous system lymphoma (PCNSL) describes a malignant extranodal non-Hodgkin’s lymphoma (NHL) whose sole site of involvement is, by definition, the central nervous system. Most PCNSL cases present in the supratentorial space, most commonly in the frontal or temporo-parietal lobes, followed by the basal ganglia. Rarely, the disease may present in the cerebellum, brainstem or even the spinal cord. The disease may include the eyes and leptomeninges. PCNSL must be differentiated from systemic NHL with metastasis to the central nervous system.

Handbook of Experimental Pharmacology, 1999

The study of neurotrophic factors (NFs) has become one of the most rapidly evolving and expanding... more The study of neurotrophic factors (NFs) has become one of the most rapidly evolving and expanding fields in the contemporary neurosciences. NFs are growth factors that enhance the survival, maintenance, differentiation and repair of neural cells (Levi-Montalcini 1987). NFs also increase neurite out-growth and neurotransmitter production. The neurons derive neurotrophic support either by means of retrograde transport from the “target cells” they innervate or from anterograde trophic support of presynaptic terminals. Glial cells, like Schwann cells, astrocytes and oligodendrocytes do provide NFs as well.

Annals of Oncology, 2017

immune checkpoint inhibitors is PD-L1 expression status and this can change over time with the ef... more immune checkpoint inhibitors is PD-L1 expression status and this can change over time with the effect of therapies like chemotherapy and radiotherapy. The aim of this study is to determine whether PD-L1 expression status changes in recurrent gliomas after chemoradiotherapy and the impact of this change on survival. Methods: PD-L1 expression of 29 patients was evaluated by an expert pathologist with immunohistochemistry. PD-L1 positivity was defined as expression in 1% of tumor cells. Change in PD-L1 expression status was defined as an absolute 5% difference between two resections. Results: Of the 29 patients, 15 patients (51.7%) had PD-L1 expression in 1% of tumor cells and 7 patients (24.1%) had PD-L1 expression in 10% of tumor cells at diagnosis. Median survival of patients with baseline PD-L1 <%10 was 26 months, and in patients with PD-L1 %10 was 18 mo (P ¼ 0.063). The PD-L1 status did not change in 17 patients (58.6%). 8 patients had PD-L1 negative tumors both at diagnosis and at recurrence, while 9 patients had PD-L1 positive tumors both at diagnosis and at recurrence. In 6 patients (20.7%) a negative-to-positive switch and in 6 patients (20.7%) a positive to negative switch were seen. The change in PD-L1 status over time was not statistically significant. The change of PD-L1 over time did not influenced overall survival of the patients (P ¼ 0.45). Conclusions: The PD-L1expression status changes in more than 40% of high grade glial tumors at recurrence after receiving chemotherapy and radiotherapy. So immune responsiveness of glial tumors can be modified by treatments. As the patients in this study did not receive immunotherapy after recurrence, the change in PD-L1 expression probably did not affect survival.

New England Journal of Medicine

Neurology

Background and Objectives Patients with a new diagnosis of cancer carry an increased risk of acut... more Background and Objectives Patients with a new diagnosis of cancer carry an increased risk of acute ischemic stroke (AIS), and this risk varies depending on age, cancer type, stage, and time from diagnosis. Whether patients with AIS with a new diagnosis of neoplasm represent a distinct subset from those with a previously known active malignancy remains unclear. We aimed to estimate the rate of stroke in patients with newly diagnosed cancer (NC) and previously known active cancer (KC) and to compare the demographic and clinical features, stroke mechanisms, and long-term outcomes between groups. Methods Using 2003–2021 data from the Acute STroke Registry and Analysis of Lausanne registry, we compared patients with KC with patients with NC (cancer identified during AIS hospitalization or within the following 12 months). Patients with inactive and no history of cancer were excluded. Outcomes were the modified Rankin scale (mRS) score at 3 months and mortality and recurrent stroke at 12 m...

Revue médicale suisse, May 18, 2022

Revue Médicale Suisse, 2017

La nouvelle classification OMS 2016 des tumeurs du système nerveux central amène un grand renouve... more La nouvelle classification OMS 2016 des tumeurs du système nerveux central amène un grand renouveau puisqu’elle prend maintenant en compte des données de biologie moléculaire et aboutit à un « diagnostic intégré ». Elle définit ainsi des groupes diagnostiques plus homogènes en termes de pronostic et de valeur prédictive à un traitement, notamment pour les gliomes. Après un rappel sur le concept de cette nouvelle classification, les notions de base sur la génétique moléculaire des gliomes et l’application pratique du diagnostic intégré, une analyse de l’impact de cette classification sur le diagnostic et le devenir des gliomes portés à l’Institut universitaire de pathologie du CHUV d’octobre 2015 à novembre 2016 est rapportée.

Objective: Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor... more Objective: Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor in adults and the diagnosis is devastating to patients and their families. Treatment includes many modalities such as surgery, radiation, chemotherapy and tumor treating fields (TTFields). The latter is[for full text, please go to the a.m. URL]

Journal of Clinical Oncology, 2006

1532 Background: Matrix metalloproteinases have been associated with angiogenesis, tumor infiltra... more 1532 Background: Matrix metalloproteinases have been associated with angiogenesis, tumor infiltration and metastases formation in systemic lymphoma. Disease status in PCNSL is determined by brain MRI; however it may be inconclusive and non-invasive tests to evaluate disease status would be useful. This study was designed to determine whether circulating levels of MMP-9 could be related to disease status in PCNSL. Methods: Circulating levels of MMP-9 were determined by ELISA and correlated with disease status assessed by MRI in a prospective longitudinal study. The disease status was classified as no evidence of disease (CR) versus active disease (AD). Results: We enrolled 18 PCNSL patients and obtained 93 blood samples (median 6 per patient, range 1–10) from August 2002 to December 2005. When in CR (12 patients, 59 samples), the mean MMP-9 level was 205.5 ± 19.1 ng/ml (median 162.3 ng/ml, range: 35.9–649.1 ng/ml). MMP-9 levels were significantly higher in AD (16 patients, 34 samples...

Journal of Clinical Oncology, 2016

TPS2083Background: Therapeutic options are limited for refractory/relapsed adult medulloblastoma ... more TPS2083Background: Therapeutic options are limited for refractory/relapsed adult medulloblastoma with activation of sonic hedgehog pathway (SHH-MB). Inhibition of this pathway may offer an attracti...

Journal for ImmunoTherapy of Cancer, 2019

Background: Immune checkpoint inhibitors (ICPis) have revolutionised the treatment of melanoma by... more Background: Immune checkpoint inhibitors (ICPis) have revolutionised the treatment of melanoma by significantly increasing survival rates and disease control. However, ICPis can have specific immune-related adverse events, including rare but severe neurological toxicity. Case presentation: We report a 44-year-old man diagnosed with stage IIIB melanoma who developed metastatic disease (pulmonary and brain metastases) and was treated with stereotactic radiosurgery and nivolumab immunotherapy. He developed asymptomatic multifocal diffuse white matter lesions consistent with active central nervous system demyelination seen on brain MRI. One month after cessation of the immunotherapy, spontaneous regression of the demyelinating lesions was observed, suggesting a nivolumab-related toxicity. Conclusion: We report the first case of a melanoma patient with an asymptomatic and spontaneously reversible central nervous system demyelination following nivolumab immunotherapy. This case highlights the need for better recognition of such atypical and rare neurological toxicities which could be mistaken for progressive brain metastases. Early recognition and appropriate management are crucial to reduce severity and duration of these toxicities, especially for patients with less favourable evolution.

Clinical Neurology and Neurosurgery, 2019

The management of women with brain tumors in the early post-partum period may be demanding as the... more The management of women with brain tumors in the early post-partum period may be demanding as the pathophysiological changes that occur during pregnancy may also manifest in the early post-partum period. The aim of our paper is to report a case of late-onset post-partum pre-eclampsia after brain tumor surgery, complicated by posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS). Hemicraniectomy and intensive care management were necessary to obtain a favorable neurological outcome. The inherent literature on the subject is also analyzed through a systematic research. This is the first case of supratentorial decompressive hemicraniectomy in post-partum PRES, while there has been only one other case of posterior fossa decompression described in this cohort of patients. PRES and RCVS can complicate the neurosurgical management of women in the postpartum period. A careful evaluation of the clinical presentation is necessary as in some particular cases an aggressive medical and surgical treatment is required to obtain a favorable outcome.

Clinical Research (Excluding Clinical Trials), 2019

Introduction: Tumor Treating Fields (TTFields) are alternating electric fields delivered via tran... more Introduction: Tumor Treating Fields (TTFields) are alternating electric fields delivered via transducer arrays placed on the scalp The EF-14 [NCT00916409] trial showed improved survival outcomes in newly diagnosed Glioblastoma (GBM) patients treated with TTFields plus Temozolomide (TMZ) versus TMZ alone We analysed EF-14 data to test the hypothesis that because TTFields delivery is planned to optimize dose at the tumor bed: TTFields treated patients are more likely to exhibit distal progressions, including progression to the infratentorium, the region where TTFields dose is minimal when planning treatment to target primary tumors in the supratentorium Tumor growth rates are slower in patients treated with TMZ+TTFields Methods: Patients on treatment for more than two months who exhibited radiological progression were included in the study (treatment: N=280/466, control: N=122/229) Regions of enhancing tumor, necrosis and resection were contoured on T1 contrast MRIs taken at baseline and at the date of first progression reported by the treating center Progressions were classified into three groups: Local progressions: 3 mm from the original tumor or resection cavity; Combined local and distal progressions: both local and distal progressions were visible The growth rate of the tumor was estimated and the distance between the original lesions and new distal lesions was measured Patients with (distal) infratentorial progression were identified. Results: More cases of non local (distal or combined local and distal) progression were observed in the treatment arm The difference between the groups was not statistically significant (69/280 vs 23/122 P Conclusions: This imaging analysis of the EF-14 Phase III trial demonstrates that adding TTFields to TMZ has substantial impact on GBM growth patterns and rate In addition to prolongation of survival times during TTFields treatment, this is another validation for the local efficacy of TTFields therapy TTFields increases local control of tumor growth, emphasizing the need for adaptive treatment after progression to control progressing disease Further studies are needed to elucidate the association between progression and TTFields dose distributions. Citation Format: Suriya Jeyapalan, Steven A. Toms, Andreas Hottinger, Lawrence Kleinberg, Erqi Pollom, Scott G. Soltys, Martin Glas. Tumor Treating Fields alters progression patterns in glioblastoma: An imaging analysis of the EF-14 Phase III trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT205.

Journal of Clinical Oncology, 2016

e14123Background: Bromodomains (BRD) bind to acetylated lysine residues on histone tails and are ... more e14123Background: Bromodomains (BRD) bind to acetylated lysine residues on histone tails and are directly involved in remodeling chromatin and regulating transcription, thus representing a potentially important anticancer target. MK-8628 is a synthetic small molecule targeting BRD2, 3 and 4 of the tandem-BRD-containing family of transcriptional regulators, the BET proteins. It has shown cytotoxic activity in in vitro GB models. We conducted a phase IIa trial with dose optimization to determine the MTD, safety and clinical activity of MK-8628 in pts with a first GB recurrence. Methods: In the first step, a traditional 3+3 dose escalation schema was used. At first recurrence of GB, pts were treated with MK-8628 administered orally at 3 dose levels (DL1: 80 mg QD, DL2: 120 mg QD, DL3: 160 mg QD) with 4-week cycles. PK analyses were performed on day 1 of cycle 1 and residual samples were drawn on day 28. MRI assessment was performed every 2 cycles (RANO). Results: Twelve pts were included between December 201...

Current Opinion in Neurology, 2019

Purpose of review Immune checkpoint inhibitors (ICPI) and chimeric antigen receptor T cells (CAR-... more Purpose of review Immune checkpoint inhibitors (ICPI) and chimeric antigen receptor T cells (CAR-T) represent novel therapies recently approved to treat a number of human cancers. As both approaches modulate the immune system, they can generate a number of immune-related adverse events (irAEs), including a large spectrum of novel neurological toxicities. These are of special interest given their potential severity and risk of compromising further oncologic treatment. We aim to provide a comprehensive review of the literature and discuss their optimal management. Recent findings In contrast to irAEs involving other organs, neurological complications of ICPI are uncommon, may present throughout the course of treatment and involve the peripheral and central nervous system, including polyneuropathy, myositis, myasthenia gravis, demyelinating polyradiculopathy, myelitis, encephalitis and others. If started early, ICPI-related neurologic irAEs are usually responsive to steroids. In contra...

Neuro-Oncology, 2016

BACKGROUND: Tumor Treating Fields (TTFields) is an established, frequency-tuned, anti-mitotic, ph... more BACKGROUND: Tumor Treating Fields (TTFields) is an established, frequency-tuned, anti-mitotic, physical treatment modality that acts in metaphase, anaphase and telophase. TTFields are delivered to the brain by a patient operated, portable medical device (Optune™, Novocure Ltd.). An international, multicenter, prospective, randomized phase 3 trial (EF-14) was initiated in 2009 to test the efficacy and safety of combining TTFields with temozlomide (TMZ) compared to TMZ alone following radiation therapy with adjuvant TMZ in patients with newly diagnosed GBM. Results of a protocol pre-specified successful interim analysis on the first 315 patients randomized has been reported (Stupp et al. JAMA 2015). Here we report the main outcomes of all 695 patients enrolled with a mature minimum follow-up of 18 month (median follow-up 36 months) for all patients (Range 19–80 months).

Current Opinion in Neurology, 2016

Neurooncology is a fascinating field that requires very different capacities: its first mission i... more Neurooncology is a fascinating field that requires very different capacities: its first mission is to insure the management and diagnosis of primary central nervous system tumors as well as metastases of systemic cancers of the brain and spinal cord. The management of those tumors is highly complicated and requires the input and knowledge from experts of multiple medical specialties including neurology, oncology, neurosurgery, radiation oncology, neuroradiology and neuropathology. Because of this, a truly multidisciplinary team that is able to consider all aspects of the management of the patient is essential. Every single one of these specialties has seen an important progress in recent years. This is nicely illustrated in the present issue with two specific topics. Leptomeningeal dissemination is a common but often poorly understood complication of systemic cancer. It deserves a complete review of the current state of the art of its management. Finally, 2016 has been marked by a series of key publications of randomized trials for low-grade gliomas. These findings and how they might change daily practice are summarized in this issue. On the other hand, the second mission of neurooncology is the identification and management of

Brain and Spine Surgery in the Elderly, 2017

Primary central nervous system lymphoma (PCNSL) describes a malignant extranodal non-Hodgkin’s ly... more Primary central nervous system lymphoma (PCNSL) describes a malignant extranodal non-Hodgkin’s lymphoma (NHL) whose sole site of involvement is, by definition, the central nervous system. Most PCNSL cases present in the supratentorial space, most commonly in the frontal or temporo-parietal lobes, followed by the basal ganglia. Rarely, the disease may present in the cerebellum, brainstem or even the spinal cord. The disease may include the eyes and leptomeninges. PCNSL must be differentiated from systemic NHL with metastasis to the central nervous system.

Handbook of Experimental Pharmacology, 1999

The study of neurotrophic factors (NFs) has become one of the most rapidly evolving and expanding... more The study of neurotrophic factors (NFs) has become one of the most rapidly evolving and expanding fields in the contemporary neurosciences. NFs are growth factors that enhance the survival, maintenance, differentiation and repair of neural cells (Levi-Montalcini 1987). NFs also increase neurite out-growth and neurotransmitter production. The neurons derive neurotrophic support either by means of retrograde transport from the “target cells” they innervate or from anterograde trophic support of presynaptic terminals. Glial cells, like Schwann cells, astrocytes and oligodendrocytes do provide NFs as well.