How we treat primary central nervous system lymphoma.

Primary diffuse large B-cell (DLBCL) lymphoma of the central nervous system (CNS) (PCNSL) is a new lymphoma entity, recognized by the 2017 WHO classification of hematopoietic and lymphoid tumors. Unlike systemic DLBCL, the use of anthracycline-based chemotherapy combinations is associated with disappointing outcomes, due to low CNS bioavailability of related drugs. Therefore, international researchers investigated alternative strategies, mostly including drugs able to cross the blood-brain-barrier at low or high doses, with a progressive improvement in survival. Some effective chemotherapy combinations of high-dose methotrexate (HD-MTX) with alkylating agents and rituximab with or without cytarabine have been tested in international randomized trials and represent the induction treatment in everyday practice, with some variations among different geographical areas. In patients aged 70 years or younger, MATRix (HD-MTX/cytarabine/thiotepa/rituximab) chemotherapy followed by consolidative high-dose chemotherapy plus autologous stem cell transplantation or whole-brain irradiation has been associated with a significant improvement in overall survival. Other treatment options, such as non-myeloablative high-dose chemotherapy, oral drug maintenance, and some targeted drugs like ibrutinib or lenalidomide, are being tested in high-level international trials. These steps toward further effective treatments are motivated by an incessant search for less neurotoxic options. Thanks to international cooperation, we can affirm that PCNSL is a potentially curable tumor, especially in young patients. However, several questions remain unanswered: the optimal treatment for elderly patients as well as the management of intraocular and meningeal disease require further scientific efforts. Beside treatments, advances on molecular and radiological diagnostic tools will increase our knowledge of this disease, allowing the possibility to anticipate diagnosis and to better categorize patients' responses. This article analyzes the available literature in this setting and provides evidence-based recommendations for the management of PCNSL patients.

A Monte Carlo model of synchrotron radiotherapy shows good agreement with experimental dosimetry measurements: Data from the imaging and medical beamline at the Australian Synchrotron.

Experimental measurement of Synchrotron Radiotherapy (SyncRT) doses is challenging, especially for Microbeam Radiotherapy (MRT), which is characterised by very high dynamic ranges with spatial resolutions on the micrometer scale. Monte Carlo (MC) simulation is considered a gold standard for accurate dose calculation in radiotherapy, and is therefore routinely relied upon to produce verification data. We present a MC model for Australian Synchrotron's Imaging and Medical Beamline (IMBL), which is capable of generating accurate dosimetry data to inform and/or verify SyncRT experiments. Our MC model showed excellent agreement with dosimetric measurement for Synchrotron Broadbeam Radiotherapy (SBBR). Our MC model is also the first to achieve validation for MRT, using two methods of dosimetry, to within clinical tolerances of 5% for a 20×20 mm2 field size, except for surface measurements at 5 mm depth, which remained to within good agreement of 7.5%. Our experimental methodology has allowed us to control measurement uncertainties for MRT doses to within 5-6%, which has also not been previously achieved, and provides a confidence which until now has been lacking in MRT validation studies. The MC model is suitable for SyncRT dose calculation of clinically relevant field sizes at the IMBL, and can be extended to include medical beamlines at other Synchrotron facilities as well. The presented MC model will be used as a validation tool for treatment planning dose calculation algorithms, and is an important step towards veterinary SyncRT trials at the Australian Synchrotron.

Vestibular assessment in patients with vestibular schwannomas: what really matters?

Vestibular function is often underdiagnosed in vestibular schwannomas (VS). To evaluate it in a selected group of patients harbouring vestibular schwannomas, 64 patients were included in this study, recruited between March 2008 and June 2011 at our institution. All patients underwent Gd-enhanced MRI and complete neurotological evaluation before gamma knife surgery. Morphological measurements included Koos Classification and quantification of internal acoustic canal filling in length and diameter. Cochlear and vestibular functions were assessed considering pure tone and speech audiometry, bedside examination and caloric test by videonystagmography. A statistical analysis was performed to find possible correlations between morphological and cochleovestibular data. Patients with a higher intracanalicular length (ICL, mean value 8.59 and median 8.8 mm) of the tumour presented a higher value of UW than the subgroup with a lower length (51.9 ± 24.3% and 38.8 ± 18.1% respectively, p = 0.04), while no difference was detected for pure tone audiometry (PTA) values (50.9 ± 22.3 db and 51.1 ± 28.9 db respectively). Patients with a higher ICL also presented a higher rate of positive HIT (88% and 60% respectively, p = 0.006). Patients with a higher value of intracanalicular diameter (ICD, mean value 5.22 and median 5.15 mm) demonstrated higher values of UW (50.2 ± 29.1% and 39.3 ± 21% respectively, p = 0.03), but not different PTA (50.2 ± 29.1 db and 51.9 ± 29.9 db respectively). Finally, patients with a positive head impulse test (HIT) demonstrated significantly higher values of unilateral weakness (UW) (p = 0.001). Vestibular disorders are probably underdiagnosed in patients with VS. ICL and ICD seem to be the main parameters that correlate with vestibular function. Also, in case of small intracanalar T1 VS a slight increase of these variables can result in significant vestibular impairment. The data reported in the present study are not inconsistent with the possibility of proactive treatment of patients with VS.

Review of cerebellopontine angle medulloblastoma.

Cerebellopontine angle (CPA) medulloblastomas (MB) are rare lesions with few cases previously described in the literature. We report two further cases of CPA MB. The patients were a 22-year-old man and a 26-year-old woman with a mass developing in the CPA. The preoperative radiological diagnosis was vestibular schwannoma in the first case and petrosal meningioma in the second case. The patients were operated on through a retrosigmoid approach. The intraoperative findings revealed an intra-axial tumour and the histological diagnosis was classic type of MB in both cases. We review the literature and discuss pathological and radiological features and possible pathogenesis of CPA MB, underlining the necessity to consider MB in the differential diagnosis of CPA lesions.

[Delivery induction with slow-release dinoprostone in clinical practice: results of a clinical protocol]. / L'induzione del parto con prostaglandine a lento rilascio nella pratica clinica: risultati di un protocollo clinico.

AIM: The aim of this paper was to evaluate the feasibility of a protocol for the induction of delivery with slow-release dinoprostone in women with unfavourable cervix. METHODS: Indications for the induction were: pregnancy beyond 40 weeks, amniotic fluid index (AFI) <5, premature rupture of membranes, intrauterine growth retardation, or adverse maternal conditions. Eligibility criteria were: single pregnancy, cephalic presentation, Bishop Score <4, no previous uterine scar. Slow-release vaginal insert containing dinoprostone 10 mg was used to induce delivery according to a dedicated protocol agreed between clinicians and midwifes. Dinoprostone induction failure was defined as no cervical dilation >3 cm at the removal of the insert. RESULTS: One-hundred-nineteen patients were enrolled. The onset of labour was obtained in 102 (85.7%) patients, 98 (82.3%) with the insert only, and in 4 (3.3%) after the sequential administration of prostaglandins and oxitocin. The mean interval between insert application and delivery was 16.85±11.48 hours. Vaginal delivery was reported in 87 (73.1%) women, whereas Cesarean was necessary in 32 (26.9%) patients [29 nulliparous]. Cesarean section was also required in 15/98 (15.3%) women who responded to prostaglandins and in 17/21 (80.9) non-responders. Protocol violations occurred in 11 (9.2%) patients. Uterine hyperstimulation occurred in 4 (3.3%) patients. CONCLUSION: Induction of delivery with slow-release dinoprostone seems a feasible option, characterized by high efficacy, good adherence to protocol, low incidence of adverse events and easy management. In our opinion the high compliance of the gynecologists and midwifes is based on the insert handiness.

Intra-cavitary dosimetry for IMRT head and neck treatment using thermoluminescent dosimeters in a naso-oesophageal tube.

Complex intensity-modulated radiation therapy (IMRT) treatment plans require rigorous quality assurance tests. The aim of this study was to independently verify the delivered dose inside the patient in the region of the treatment site. A flexible naso-gastric tube containing thermoluminescent dosimeters (TLDs) was inserted into the oesophagus via the sinus cavity before the patient's first treatment. Lead markers were also inserted into the tube in order that the TLD positions could be accurately determined from the lateral and anterior-posterior electronic portal images taken prior to treatment. The measured dose was corrected for both daily linac output variations and the estimated dose received from the portal images. The predicted dose for each TLD was determined from the treatment planning system and compared to the measured TLD doses. The results comprise 431 TLD measurements on 43 patients. The mean measured-to-predicted dose ratio was 0.988 +/- 0.011 (95% confidence interval) for measured doses above 0.2 Gy. There was a variation in this ratio when the measurements were separated into low dose (0.2-1.0 Gy), medium dose (1.0-1.8 Gy) and high dose (>1.8 Gy) measurements. The TLD-loaded, naso-oesophageal tube for in vivo dose verification is straightforward to implement, and well tolerated by patients. It provides independent reassurance of the delivered dose for head and neck IMRT.

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial.

BACKGROUND: Continuous research into new strategies and chemotherapy agents for the treatment of malignant high-grade gliomas have led to the synthesis of a new chemotherapy drug, temozolomide (TMZ), with a lower toxicity profile compared to conventional chemotherapy agents, such as nitrosoureas. Temozolomide is an oral alkylating chemotherapy agent licensed for the treatment of recurrent high-grade gliomas, anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Because of its favorable pharmacokinetic and pharmacodynamic properties and improved tolerability, TMZ is now under investigation for concomitant use with radiotherapy in patients with newly-diagnosed GBM. We present a phase II clinical trial investigating the efficacy and safety of radio-chemotherapy combined treatment using TMZ, followed by six cycles of adjuvant chemotherapy with TMZ, in patients with newly-diagnosed GBM who have undergone debulking surgery or biopsy only. PATIENTS AND METHODS: Twenty-one patients with newly histologically-diagnosed GBM were enrolled into this phase II clinical trial. In phase I of the study, TMZ (75 mg/m2/day per 7 days/wk for 6 weeks) was orally administered to patients concomitantly with radiotherapy (RT) (2 Gy per fraction once daily, per 5 days/wk for 6 weeks). In phase II of the study, four weeks after completion of RT, a monochemotherapy using TMZ was administered at the dosage of 200 mg/m2/day per 5 days every 28 days for 6 cycles. Primary end-points were the safety and tolerability profile of this two-phase combined treatment and secondary end-points were the objective response and survival rates at twelve months and eighteen months from study entry. RESULTS: The one-year survival rate of patients treated with the investigated multimodality treatment was 58% and median survival time was 15.7 months. Concomitant RT plus TMZ (phase I) followed by adjuvant TMZ (phase 2) were well-tolerated; indeed, nonhematological adverse events were rare and mild to moderate in severity; grade 3 and 4 neutropenia and thrombocytopenia were the major-related hematological side-effects observed in only 2 and 3 of all patients in phase I and 4 patients in phase II. We found that the combination of radio- and chemo-therapy, in phase I of the study did not significantly increase the incidence and severity of hematological toxicity caused by the adjuvant TMZ-based chemotherapy administered in phase II of the study. CONCLUSION: The investigated multimodality treatment regimen was well-tolerated and prolonged survival while improving patients' quality of life.

Brain metastases from hepatocellular carcinoma. A case report.

Brain metastasis from hepatocarcinoma are a decidedly rare occurrence in countries where this pathology is most frequent. The authors describe a case of metastases from hepatocellular carcinoma in a patient suffering from post-HBV hepatic cirrhosis with hemorrhagic onset. The "stroke-like" presentation of the cerebral localization of the disease can be explained by both the important vascularization of the tumor and the frequent hemocoagulative alterations caused by the cirrhosis. The importance of diagnostic neuroradiology is briefly addressed, with reference to the fundamental role played by MRI. Surgery of these lesions does not present any particular technical problems as long as they are located in accessible areas and the patient's general and neurological conditions allow it. Postoperative radiotherapy seems to improve the quality and quantity of residual life, although the number of patients described in the literature is too small to draw any definite conclusion. Promising molecular biology studies are under way to evaluate the role of oncosuppresor gene expression in hepatocarcinogenesis and in the way the disease spreads.

Use of spiral computerized tomography angiography in patients with cerebral aneurysm. Our experience.

BACKGROUND: The purpose is to highlight the usefulness of CT angiography (CTA) in the diagnosis and surgical treatment of cerebral aneurysms. METHODS: Thirty-one patients with subarachnoid haemorrhages were subjected to CT angiography and in those cases where this test did not reveal the aneurysm or did not supply sufficient information relating to it, subsequently a digital subtraction angiography was also performed. Each aneurysm-positive CTA was re-processed using the 3-D techniques, with the neuro-radiologist and the neuro-surgeon working in close co-operation. RESULTS: In 27 cases the CTA diagnosed an aneurysm, and in the 4 cases where no vascular malformations were revealed, also the traditional angiography did not show any pathology. In 17 out of 18 cases operated on in order to clip the aneurysm, the CTA supplied all the information needed for the surgery and it was possibile to reconstruct images similar to those of the surgical field. This led to improvement in the programming of the surgical intervention; in 1 case only was it also necessary to perform the DSA before the operation. CONCLUSIONS: CT angiography, because it is non-invasive, easy to perform, diagnostically reliable, and because the 3-D re-constructions offer the chance to create images of the possible operating field, is the first-choice test to be adopted in the treatment of subarachnoid haemorrhages, even though in some cases the use of the traditional angiography is still necessary and should be carried out whenever the CTA does not reveal vascular malformations.

The early growth response gene EGR-1 behaves as a suppressor gene that is down-regulated independent of ARF/Mdm2 but not p53 alterations in fresh human gliomas.

PURPOSE: EGR-1 is an immediate early gene with diverse functions that include the suppression of growth. EGR-1 is down-regulated many cancer cell types, suggesting a tumor suppressor role, and may critically involve the p53 pathway. The aim of this work was to measure the expression of EGR-1 and the p16/INK4a/ARF-Mdm2-p53 pathway status in fresh human gliomas. EXPERIMENTAL DESIGN: Thirty-one human gliomas with different grades of malignancy were investigated for Egr-1 mRNA and the protein expression, frequency, and spectrum of p53 gene mutations, mdm2 gene amplification, and p16/INK4a/ARF allele loss. RESULTS: The amplification of Mdm2 and the deletion of the p16/INK4a gene was found in 3 and 5 cases, respectively, whereas mutations of p53, including two novel mutations, were observed in 10 other cases. The three types of changes occurred strictly mutually exclusively, emphasizing that these genes operate in a common pathway critical to glioma progression. EGR-1 mRNA was significantly down-regulated in astrocytomas (14.7 +/- 5.1%) and in glioblastomas (33.6 +/- 10.0%) versus normal brain. Overall, EGR-1 mRNA was strongly suppressed (average, 15.2 +/- 13.9%) in 27 of 31 cases (87%), independent of changes in p16/INK4a/ARF and Mdm2; whereas 4 of 31 cases with residual EGR-1 expression as well as the highest EGR-1 variance segregated with p53 mutations. Immunohistochemical analyses confirmed the suppression of EGR-1 protein. CONCLUSIONS: These results indicate that EGR-1 is commonly suppressed in gliomas independent of p16/INK4a/ARF and Mdm2 and that suppression is less crucial in tumors bearing p53 mutations, and these results implicate an EGR-1 growth regulatory mechanism as a target of inactivation during tumor progression.

Single brain metastasis from thyroid cancer: report of twelve cases and review of the literature.

Brain metastases from thyroid carcinoma is unusual, with a frequency of 1%. We report twelve patients, with single brain metastases and with a karnofsky performance scale score >60 at admission. No metastasis was seen during the uptake of iodine-131, even in the cases from differentiated thyroid carcinoma, suggesting absence of differentiation between primary and metastasic disease. The histopathology of thyroid carcinomas was anaplastic in five cases, differentiated in six, and medullary in one. Only in four patients, brain was the unique site of metastatic spread; in others, bones and lungs were also involved. All metastases were surgically removed, and all patients were treated with radiotherapy (45 Gy) in the postoperative course. The survival average was 19.8 months, and the quality of life was satisfactory in all patients. One patient remained alive till 5 years. Anaplastic histopathology and size of the primitive, and also bone involvement of thyroid disease were significant risk factors in our cases (p < 0.05). According to the literature, surgery is the best therapeutical choice. Alternative strategies in the management of brain metastasis, such as iodine-131 therapy, are discussed, paying particular attention to the relevant side effects.

Human herpesvirus 6 infection in neoplastic and normal brain tissue.

The presence and variant distribution of human herpesvirus 6 (HHV-6) was investigated by a nested polymerase chain reaction (PCR) in 118 biopsies from patients affected by nervous tissue tumor (115 primary tumors and 3 metastasis) and in 31 autopsy samples from the brain of healthy individuals. HHV-6 DNA sequences were detected in normal and neoplastic nervous tissue at a frequency of 32% and 37%, respectively. In both tissues, variant A was three times more frequent than the variant B. Peripheral blood lymphocytes (PBLs) derived from seven tumor affected patients contained the same variant as their respective brain sample, as judged by PCR. The expression of HHV-6 encoded immediate early protein p41 was detected by immunohistochemistry in neoplastic but not in normal brain. This may reflect viral reactivation from latency in immunocompromised patients. The seroepidemiological data indicated a frequency distribution of anti-HHV-6 antibodies in patients with brain tumors similar to that found in healthy donors.

Cavernous angiomas of the nervous system in Italy: clinical and genetic study.

We performed a clinical and genetic study of patients affected by cavernous angiomas (CA) of the nervous system. We examined initial signs and symptoms in sporadic and familial cases. We obtained clinical, neuroimaging and genetic data on 15 Italian patients with CA of the nervous system with positive, doubtful or apparently negative family history. Genetic markers surrounding three different gene regions (7q, 3q and 7p) were analysed. In one small family, genetic linkage was consistent with all chromosome loci. In another family with the unusual association of cerebral and spinal CA, linkage with chromosome 7q and, likely, 7p was excluded, while linkage with locus 3q was possible. Our results indicate that Italian families with CA may show genetic heterogeneity. Non-specific and subtle onset symptoms hide the presence of CA within families. Patients with multiple CA may have silent cerebral lesions confirming the low penetrance of clinical signs in spite of radiological ones.

Cerebral metastasis from ovarian carcinoma. Some observations about treatment.

Systemic metastases from ovarian carcinoma are frequent, but they rarely affect the central nervous system. The treatment of this type of metastases in not clear. Two cases of solitary cerebral metastasis from ovarian carcinoma are reported. Two patients, submitted to therapeutic protocol established for ovarian carcinoma, presented after 17 and 25 months respectively the appearance of symptoms from brain solitary metastasis without other metastases. They underwent surgery, radiotherapy and chemotherapy for solitary cerebral metastasis. Treatment of the brain lesion resulted in KPS improvement (KPS = 90) and survival was 16 and 30 months, respectively. From the 2 cases presented and the review of the literature, it appears that a better outcome may be obtained by a combined treatment of metastases, including surgery, radiotherapy and chemotherapy.

Intracerebral schwannoma. Case report.

A case of intraparenchymal schwannoma is presented. A 61-year-old woman, with stigmata of von Recklinghausen's neurofibromatosis (NF-2), presented with a history of weakness of the right lower limb for 2 months. She was investigated by MR which showed a circular mass with a maximum diameter of 5 cm in the right parieto-occipital lobe. The tumor was removed in toto via a left parieto-occipital craniotomy. The patient was discharged two weeks after the operation and remains well now 2 years later. The clinical and neuroradiological findings of reported intraparenchymal schwannomas, including the case reported here, are discussed.

[Epidermoid cyst of the cranial vault. Neuroradiological and therapeutic considerations]. / Cisti epidermoide della volta cranica. Considerazioni neuroradiologiche e terapeutiche.

AIM: Intradiploic epidermoid cyst is a slow-growing tumor affecting only rarely the cranial bones. PATIENT: The authors describe a case of intradiploic epidermoid cyst of the cranial vault in which there was a predominantly intracranial extension. Roentgenographic and CT findings do not permit a differential diagnosis. Complete removal of the cyst and its capsule was accomplished, with complete recovery. CONCLUSION: Total removal oft the tumor and its capsule is associated with a very good long-term prognosis without recurrences.

Sarcoma metastatic to the brain: a series of 15 cases.

METHODS: We report on 15 patients surgically treated for intraparenchymal brain metastases from sarcoma, including six osteosarcomas, five leiomyosarcomas, two malignant fibrous histiocytomas, and two alveolar soft-part sarcomas (ASPS). RESULT: Median survival after craniotomy was 9.3 months. Patients with a preoperative Karnofsky performance score of > 70 survived for 12.8 versus 5.3 months for those with a Karnofsky performance score < 70 (p=0.03). Patients with evidence of only lung metastases at the time of surgery (nine cases) survived 8.6 months, which was similar to the 10.4-month survival for patients with disease limited to the brain (p=0.1). The two patients with alveolar soft-part sarcomas are alive at 15 and 20 months after surgery. CONCLUSION: We conclude that surgery is effective in treating selected patients with sarcoma metastatic to the brain and that patients with metastasis from ASPS may have a relatively good prognosis if they are surgically treated. The complete removal of all brain metastases and a Karnofsky performance score > 70 are associated with a favorable prognosis; the presence of concurrent lung metastases is not a contraindication to surgery.