Reduction of immunosuppression combined with whole-brain radiotherapy and concurrent systemic rituximab is an effective yet toxic treatment of primary central nervous system post-transplant lymphoproliferative disorder (pCNS-PTLD): 14 cases from the prospective German PTLD registry.

Post-transplant lymphoproliferative disorders (PTLD) exclusively affecting the central nervous system-primary CNS-PTLD (pCNS-PTLD)-are rare. There is no standard therapy, and previous case series have included heterogeneous treatment approaches. We performed a retrospective, multi-centre analysis of 14 patients with pCNS-PTLD after solid organ transplantation (SOT) treated in the prospective German PTLD registry with reduction of immunosuppression (RI), whole-brain radiotherapy (WBRT), and concurrent systemic rituximab between 2001 and 2018. Twelve of fourteen patients were kidney transplant recipients and median age at diagnosis was 65 years. Thirteen of fourteen cases (93%) were monomorphic PTLD of the diffuse large B-cell lymphoma type, and 12/13 were EBV-associated. The median dose of WBRT administered was 40 Gy with a median fraction of 2 Gy. The median number of administered doses of rituximab (375 mg/m2) IV was four. All ten patients evaluated responded to treatment (100%). Median OS was 2.5 years with a 2-year Kaplan-Meier estimate of 63% (95% confidence interval 30-83%) without any recorded relapses after a median follow-up of 2.6 years. Seven of fourteen patients (50%) suffered grade III/IV infections under therapy (fatal in two cases, 14%). During follow-up, imaging demonstrated grey matter changes interpreted as radiation toxicity in 7/10 evaluated patients (70%). The combination of RI, WBRT, and rituximab was an effective yet toxic treatment of pCNS-PTLD in this series of 14 patients. Future treatment approaches in pCNS-PTLD should take into account the significant risk of infections as well as radiation-induced neurotoxicity.

Milestones in stereotactic radiosurgery for the central nervous system.

INTRODUCTION: Since Lars Leksell developed the first stereotactic radiosurgery (SRS) device in 1951, there has been growth in the technologies available and clinical indications for SRS. This expansion has been reflected in the medical literature, which is built upon key articles and institutions that have significantly impacted SRS applications. Our aim was to identify these prominent works and provide an educational tool for training and further inquiry. METHOD: A list of search phrases relating to central nervous system applications of stereotactic radiosurgery was compiled. A topic search was performed using PubMed and Scopus databases. The journal, year of publication, authors, treatment technology, clinical subject, study design and level of evidence for each article were documented. Influence was proposed by citation count and rate. RESULTS: Our search identified a total of 10,211 articles with the top 10 publications overall on the study of SRS spanning 443-1313 total citations. Four articles reported on randomized controlled trials, all of which evaluated intracranial metastases. The most prominent subtopics included SRS for arteriovenous malformation, glioblastoma, and acoustic neuroma. Greatest representation by treatment modality included Gamma Knife, LINAC, and TomoTherapy. CONCLUSIONS: This systematic reporting of the influential literature on SRS for intracranial and spinal pathologies underscores the technology's rapid and wide reaching clinical applications. Moreover the findings provide an academic guide to future health practitioners and engineers in their study of SRS for neurosurgery.

Temozolomide for central nervous system involvement in mycosis fungoides.

BACKGROUND: The central nervous system (CNS) is one of the most commonly involved sites in the systemic progression of primary cutaneous T cell lymphomas (CTCLs) such as mycosis fungoides (MF). There is no consensus on the treatment of CNS progression in CTCL, but survival of 3-6 months is suggested when methotrexate-based chemotherapy and/or CNS irradiation is used. Temozolomide is active in earlier stages of MF and readily crosses the blood-brain barrier. There are no published data on its use in MF patients with CNS involvement. METHODS: Four MF patients were treated with oral temozolomide (200 mg/m(2) per day for 5 d on a 28-day cycle) for CNS progression. Two patients received temozolomide with low-dose CNS irradiation as initial treatment, and two received temozolomide following disease progression after methotrexate-based chemotherapy and CNS irradiation. All patients received dexamethasone. RESULTS: Temozolomide was well tolerated; there were no treatment withdrawals or dose reductions caused by toxicity. Patient 1 had an excellent partial response in pre-irradiated disease. Patient 2 showed disease stabilization following irradiation. Patient 3 showed a complete response after a partial response to irradiation. Patient 4 demonstrated continued stabilization after a partial response to irradiation. Overall survival ranged from 10 to 33 months. Patient 3 remains alive and symptom-free at 23 months following treatment. CONCLUSIONS: Temozolomide following low-dose CNS irradiation appears to be well tolerated and effective in MF patients with CNS progression. It may represent a less toxic alternative to chemotherapy containing methotrexate or an option for second-line therapy.

Central nervous system involvement in acute myeloid leukemia patients undergoing hematopoietic cell transplantation.

Knowledge regarding the rate of central nervous system (CNS) involvement and risk factors for its development in acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic cell transplantation (HCT) are limited. In this study we retrospectively evaluated CNS involvement in 327 patients who underwent myeloablative HCT at our institute in which all patients have cerebrospinal fluid examined by morphology or flow cytometry before HCT. Twenty-two patients (7%) had CNS AML involvement at pre-HCT evaluation. Covariates associated with such involvement were higher WBC at diagnosis, prior CNS or other extramedullary disease, and evidence of systemic disease at pre-HCT evaluation. History of prior CNS disease and disease status at pre-HCT evaluation allowed stratification of patients into 3 risk groups: 35% (20 patients), 16% (51 patients), and 3% (256 patients) rates of pre-HCT CNS involvement. Treatment of pre-HCT CNS disease was uniformly successful regardless of whether cranial irradiation therapy was used. Perhaps as a result, presence of CNS pre-HCT had no independent influence on post-HCT outcome, which was primarily influenced by status of systemic disease at time of HCT.

Red/near-infrared irradiation therapy for treatment of central nervous system injuries and disorders.

Irradiation in the red/near-infrared spectrum (R/NIR, 630-1000 nm) has been used to treat a wide range of clinical conditions, including disorders of the central nervous system (CNS), with several clinical trials currently underway for stroke and macular degeneration. However, R/NIR irradiation therapy (R/NIR-IT) has not been widely adopted in clinical practice for CNS injury or disease for a number of reasons, which include the following. The mechanism/s of action and implications of penetration have not been thoroughly addressed. The large range of treatment intensities, wavelengths and devices that have been assessed make comparisons difficult, and a consensus paradigm for treatment has not yet emerged. Furthermore, the lack of consistent positive outcomes in randomised controlled trials, perhaps due to sub-optimal treatment regimens, has contributed to scepticism. This review provides a balanced précis of outcomes described in the literature regarding treatment modalities and efficacy of R/NIR-IT for injury and disease in the CNS. We have addressed the important issues of specification of treatment parameters, penetration of R/NIR irradiation to CNS tissues and mechanism/s, and provided the necessary detail to demonstrate the potential of R/NIR-IT for the treatment of retinal degeneration, damage to white matter tracts of the CNS, stroke and Parkinson's disease.

Successful treatment of monomorphic primary central nervous system post-transplantation lymphoproliferative disorder 5 years after kidney transplantation.

A 31-year-old man underwent living-related kidney transplantation in 2004 as a consequence of primary focal segmental glomerulosclerosis (FSGS). Four years after the transplantation, we confirmed nephrotic syndrome caused by recurrent FSGS. We performed plasmapheresis and low-density lipoprotein adsorption. We also combined steroid therapy with a reduction in the dose of tacrolimus and an increased dose of mycophenolate mofetil. The nephrotic syndrome improved dramatically with this combined therapeutic approach. However, 10 months after these treatments, he revisited our hospital because of altered consciousness. We detected multiple tumor masses in his brain that were ring enhanced on contrast magnetic resonance imaging. Consequently, we suspected primary central nervous system post-transplantation lymphoproliferative disorder (CNS-PTLD). We performed a craniotomy to biopsy the brain tumors. The biopsy specimen showed Epstein-Barr virus-associated diffuse large B-cell lymphoma. There is no definitive treatment for CNS-PTLD. Therefore, we treated the primary CNS-PTLD successfully with whole-brain radiation and discontinuation of immunosuppression therapy.

Role of radiotherapy in the treatment of neurosarcoidosis.

Neurosarcoidosis is usually managed with steroids, immunosuppressives, and other medications. Several small series suggest that radiotherapy might be useful in patients whose disease is refractory to conventional treatment. The purpose of this article is to report the outcome of 4 patients with neurosarcoidosis who were treated at the University of Florida. With long-term follow up, partial regression of disease was observed in 2 patients, stabilization of disease in 1 patient, and disease progression in 1 patient. Our experience and review of the related literature suggest the following conclusions: (1) radiotherapy is often effective in preventing the progression of local symptoms from neurosarcoidosis, but has limited application in reversing established neurologic deficits; (2) sarcoid meningitis is responsive to radiotherapy; and (3) radiation dose for the palliation of symptoms related to neurosarcoidosis is 20 to 25 Gy.

Partial irradiation of the brain.

Late radiation injury is the main dose-limiting factor for radiotherapy of tumors of the central nervous system (CNS). Clinical experience as well as analyses of complication data, both for brain necrosis and for changes in neuroimaging after radiosurgery, suggest a pronounced volume effect in the brain. However, the relationships of dose and volume to complications after irradiation of lesions in the brain have yet to be quantitatively assessed. The quantification of volume effects and the modeling of normal tissue response to partial organ irradiation of the brain are particularly demanding because of the highly differentiated and complex structure of the brain and the variety of endpoints after radiotherapy for CNS diseases. This article summarizes the existing clinical data that demonstrate a volume effect in the brain and the current state of knowledge regarding the modeling of complications following partial irradiation of the brain.

Radiation-induced meningiomas.

High dose radiation-induced meningiomas are a rare, severe and late complication of craniospinal radiotherapy for brain tumors. Radiation-induced meningiomas are, according to the literature, several times more frequent than radiogenic gliomas and sarcomas. It is suggested that every new case of radiogenic meningioma has to be reported to elucidate this particular pathologic entity with its many grey areas. In addition to high dose radiation-induced meningiomas, intracranial meningiomas were observed in patients who underwent low-dose radiation for tinea capitis in childhood, applied en mass to immigrants coming to Israel from the North Africa and the Middle East during the 1950. Authors summarize the data on radiogenic meningiomas from the literature and, as the previous radiotherapy may confer a low, but life-long risk for meningioma occurrence, they suggest that surveillance MRI after high dose cerebrospinal radiotherapy should be extended to several (3-5) decades after radiotherapy.

Radiation therapy for benign central nervous system disease.

The most common indication for the use of radiation therapy in the treatment of benign central nervous system disease is for the treatment of benign brain tumors, such as meningioma, pituitary adenoma, acoustic neuroma, arteriovenous malformation, and craniopharyngioma. Other less common benign intracranial tumors treated with radiation include chordoma, pilocytic astrocytoma, pineocytoma, choroid-plexus papilloma, hemangioblastoma, and temporal bone chemodectomas. Benign conditions, such as histiocytosis X, trigeminal neuralgia, and epilepsy, are also amenable to radiation treatment. There have also been reports of radiosurgery being used for the treatment of movement disorders and psychiatric disturbances, such as obsessive-compulsive and anxiety disorders. For benign brain tumors, radiation therapy as either primary or adjuvant therapy plays an integral role in improving local control. In the treatment of trigeminal neuralgia, epilepsy, tremor, and some psychiatric disturbances, radiosurgery may help ameliorate or eliminate some symptoms. Patients with benign central nervous system disease are expected to live a long time. As such, treatment should be highly conformal and based on three-dimensional planning using magnetic resonance imaging, computed tomography, or both. It is critical that damage to normal brain be minimized.

An innovative method for neuraxis radiotherapy using partial transmission block technique.

Whole CNS (neuraxis) radiotherapy is an important part of therapy for certain CNS tumours which seed via the CSF. Many, if not the majority, of these predominantly young patients are cured but the neuropsychometric, neuroendocrine and growth morbidity of neuraxis radiotherapy on children by conventional methods may be considerable; patients receiving such therapy at an early age often are eventually in the educationally subnormal category. Recent radiobiological data support the concept that all aspects of CNS radiation tolerance are heavily dependent on daily fraction size. We describe a new radiotherapy technique that allows lower daily fraction sizes to be delivered to the neuraxis without prejudicing the total dose to the neuraxis or primary area and without prolonging the overall treatment time. Published radiobiological data support the concept that all the major morbidities attributed to conventional neuraxis radiotherapy will be reduced by the currently described technique without reducing tumour control rates.

Adjuvant chemotherapy for primary lymphoma of the central nervous system.

Ten immunocompetent patients with primary non-Hodgkin's lymphoma of the central nervous system were treated by the neuro-oncology service at the University of California at San Francisco (UCSF). After undergoing surgery for biopsy or removal of their tumors, these patients (group 1) received irradiation with hydroxyurea followed by adjuvant chemotherapy with the combination of procarbazine, lomustine (CCNU), and vincristine. The outcome of treatment in this group was compared with that in three other groups of patients with primary CNS lymphoma: patients treated at the UCSF Cancer Research Institute who underwent surgery and radiation therapy (RT) (group 2); patients described in the literature who had surgery and RT (group 3); or patients described in the literature who had surgery, RT, and chemotherapy (group 4). Median and quartile survival times were greater in patients who received adjuvant chemotherapy (group 1, 30 and 50 months; group 4, 20 and 25 months) than in patients who did not receive chemotherapy after RT (group 2, 13 and 20 months; group 3, 15 and 24 months). These results suggest that adjuvant chemotherapy is useful in the treatment of primary CNS lymphoma.

Palliative benefit of radiation therapy in advanced ovarian cancer.

Fifty-five courses of palliative radiation therapy were given to patients with recurrent epithelial ovarian cancer previously treated with platinum-based chemotherapy. The treatments were evaluated for their effectiveness in palliating a variety of symptoms (bowel obstructions, pulmonary metastases causing dyspnea, CNS metastases causing dizziness and mental status changes, lower-extremity edema, pain, and vaginal bleeding and discharge). In addition, the time commitment to therapy and the symptom-free interval relative to the patient's survival from the initiation of radiation therapy were evaluated to assess true palliative benefit.

Primary malignant lymphomas of the central nervous system: radiotherapy results in 12 cases.

Twelve patients with primary lymphomas of the central nervous system were treated in the Department of Radiation Oncology, Yonsei University College of Medicine, between 1976 and 1987. There were seven males and five females ranging from 19 to 63 years of age. They had single (6 cases) or multiple (6 cases) discrete intracerebral nodules. All patients were treated with radiation therapy. Surgical resection was performed in five cases and intrathecal chemotherapy with methotrexate was performed in seven cases after radiotherapy. All patients except one had received whole brain irradiation with a median dose of 4000 cGy. The radiation dose for a primary tumor was 4800-6000 cGy (median 5560 cGy). Initial response to radiation was excellent with a 91.7% complete response rate, but late recurrences were noted and the median survival was 42.3 months. Intracranial recurrences were observed in two patients who received less than 4000 cGy to the whole brain without intrathecal chemotherapy. Although intracranial recurrence was not seen in the patients receiving intrathecal chemotherapy after radiation, a high incidence of necrotizing leukoencephalopathy was noted. High dose irradiation with a minimum of 4000 cGy to the whole brain and more than 5000 cGy to the primary tumor is recommended for the treatment of primary CNS lymphomas. Combined use of chemotherapy should be carefully attempted because of the increased toxicity.

Isolated central nervous system relapse in acute lymphocytic leukemia (ALL) in children. Experiences of the Swiss Pediatric Oncology Group (SPOG/SAKK) 1976-1986.

The incidence of isolated CNS-relapse in the SPOG ALL studies 1976-1986 was analyzed and the prophylaxis of meningosis leucaemica of the different studies was compared. In the SPOG ALL high-risk study 1979-1983, the incidence of isolated CNS-relapse was significantly higher (17/71, 24%) than in the other studies. In this period, radiotherapy was omitted and the prophylactic treatment consisted only of moderately high doses of intravenous methotrexate and intrathecal methotrexate. In other studies, it was shown that the prophylactic combination of CNS-radiotherapy and intrathecal methotrexate, or the periodic administration of combined intrathecal chemotherapy alone, during the whole therapy of 2 1/2 years, produced comparably good results. The prophylaxis with the combined intrathecal chemotherapy was less neurotoxic and allowed the use of a curative radiotherapy in case of a CNS-relapse.

Pseudo-pseudo-Foster Kennedy syndrome.

An 80-year-old woman presented with a classic story and findings of an anterior ischemic optic neuropathy in her left eye. Her right eye had slow and progressive decreased vision, ostensibly secondary to a cataract. However, the right eye showed slight temporal pallor of the optic disc and a superior temporal field defect was found. Her radiologic exam showed a tuberculum sella meningioma extending into the right optic canal compressing the right optic nerve. Two diseases, ischemic optic neuropathy and meningioma, in one patient may be termed a pseudo-pseudo-Foster Kennedy syndrome.