Relapse in medulloblastoma: what can be done after abandoning high-dose chemotherapy? A mono-institutional experience.

PURPOSE: We retrospectively report strategies used for medulloblastoma patients progressing after craniospinal irradiation where we aimed for: symptom control, a satisfactory quality of life, accrual in phase 1-2 trials, when available, and the first two conditions could no longer be satisfied by already experienced second-line strategies. METHODS: Surgery was used in cases of doubtful relapse or when only one site was affected. Radiotherapy was given whenever possible, especially to relieve symptoms. The main chemotherapy regimens were oral temozolomide/etoposide, intravenous (iv.) cisplatin/etoposide, iv. gemcitabine/oxaliplatin, an oral sonic hedgehog pathway inhibitor and oral melphalan. RESULTS: Between 1998 and 2011, we treated 18 patients relapsed after median 20 months. Nine had relapsed locally, four had dissemination, three single metastases, and two had one synchronous local and metastatic recurrence. Responses to chemotherapy were seen in 32% of cases. The median hospital stay for treatments/complications was 19 days. The 1- and 3-year progression-free survival (PFS) rates were 28 ± 10% and 0%, respectively, for OS, they were 44 ± 12% and 22 ± 10% but no patient was cured. The median PFS after a first relapse was 7 months (range 1-29); the median OS was 7 months (range 4-44). No patients died due to treatment toxicity. Late recurrence (more than 1-2 years after diagnosis) and involvement of single sites were favorable prognostic factors. CONCLUSIONS: Without succeeding in patients cure, we ensured them further treatment with short hospital stay thus affording low personal and social costs. The chances of cure may emerge from tailored therapies according to genetic stratification.

Real-Time Ex-Vivo Magnetic Resonance Image-Guided Dissection of Human Brain White Matter: A Proof-of-Principle Study.

OBJECTIVE: Modern neuroanatomic education should be based on interdisciplinary methods that allow an understanding of the cerebral circuitry, which is at the base of the structural connectivity. Ex-vivo MRI-guided dissection is an essential method for developing and refining the knowledge of complex 3-dimensional brain anatomy and the mutual relationships between structures and architecture of the white matter bundles. The aim of this technical note is to present a new and innovative method of studying human brain white matter. METHODS: Four adult human cerebral hemispheres were prepared according to the Klinger's method. T1-weighted and T2-weighted and fluid attenuated inversion recovery images were obtained with a 3T magnetic resonance machine. The dissection was performed in a dedicated neurosurgical laboratory equipped with a microscope and an electromagnetic neuronavigation system that guided the whole white matter dissection. RESULTS: Gyri and sulci morphology were studied in detail. The relations between superficial and inner structures were observed before and after the dissection. Gray matter was carefully removed with blunt dissectors, and the U-fibers were exposed. Afterwards, deeper association and projection fibers, such as the arcuate fasciculus, superior and inferior longitudinal fasciculus, corona radiata, extreme and external capsule, claustrum, anterior commissure, and internal capsule were visualized under high magnification. The neuronavigation system was crucial for continuously checking the whole dissection procedure to avoid any accidental excision of fibers. CONCLUSION: Image-guided neuronavigated dissection can significantly improve the quality of white matter dissection and represents a valid tool for learning the 3-dimensional anatomy of the human brain tracts.

An unusual case of tracheo-pleural fistula and cardiac metastases in oropharyngeal carcinoma: a case report and review of the literature.

BACKGROUND: Oropharyngeal cancer is frequently associated with human papilloma virus, that also represents a strong prognostic factor. Local relaps and treatment-related complications are frequent, whereas distant metastases occur in about 25% of patients. CASE PRESENTATION: A 49 years-old male presented with a loco-regionally advanced oropharyngeal squamous cell carcinoma and was treated with concomitant chemoradiation. A complete clinical and pathological response was achieved, but the occurrence of necrotising tracheo-esophagitis, with tracheo-mediastino-pleural fistula formation, further complicated the subsequent clinical course. The patient died suddenly. Autopsy revealed multiple myocardial and epicardial metastases from oropharyngeal squamous cell carcinoma. CONCLUSIONS: Even in case of a transient complete local response, the potential occurrence of severe complications and distant metastases, although infrequent, should be considered. Cardiac metastases are frequently underestimated, as they are often asymptomatic, but may lead to sudden death. Further efforts are needed to improve diagnosis and therapy in this setting.

The lateral infratrigeminal transpontine window to deep pontine lesions.

OBJECT: Surgery of brainstem lesions is increasingly performed despite the fact that surgical indications and techniques continue to be debated. The deep pons, in particular, continues to be a critical area in which the specific risks related to different surgical strategies continue to be examined. With the intention of bringing new knowledge into this important arena, the authors systematically examined the results of brainstem surgeries that have been performed through the lateral infratrigeminal transpontine window. METHODS: Between 1990 and 2013, 29 consecutive patients underwent surgery through this window for either biopsy sampling or for removal of a deep pontine lesion. All of this work was performed at the Department of Neurosurgery of the Istituto Nazionale Neurologico "Carlo Besta", in Milan, Italy. A retrospective analysis of the findings was conducted with the intention of bringing further clarity to this important surgical strategy. RESULTS: The lateral infratrigeminal transpontine window was exposed through 4 different approaches: 1) classic retrosigmoid (15 cases), 2) minimally invasive keyhole retrosigmoid (10 cases), 3) translabyrinthine (1 case), and 4) combined petrosal (3 cases). No deaths occurred during the entire clinical study. The surgical complications that were observed included hydrocephalus (2 cases) and CSF leakage (1 case). In 6 (20.7%) of 29 patients the authors encountered new neurological deficits during the immediate postoperative period. All 6 of these patients had undergone lesion removal. In only 2 of these 6 patients were permanent sequelae observed at 3 months follow-up. These findings show that 93% of the patients studied did not report any permanent worsening of their neurological condition after this surgical intervention. CONCLUSIONS: This retrospective study supports the idea that the lateral infratrigeminal transpontine window is both a low-risk and safe corridor for either biopsy sampling or for removal of deep pontine lesions.

Rare case of Cushing's disease due to double ACTH-producing adenomas, one located in the pituitary gland and one into the stalk.

UNLABELLED: We describe a patient affected by Cushing's disease due to the presence of double pituitary adenomas, one located within the anterior pituitary and the other in the infundibulum associated with a remnant of Rakthe's pouch. Cure was achieved only after the infundibulum lesion was surgically removed. CASE REPORT: A 38-year-old female presented with unexplained weight gain, hirsutism, amenorrhea, asthenia, recurrent cutaneous micotic infections and alopecia. Hormonal studies indicated Cushing's disease and MRI showed an enlarged pituitary gland with a marked and homogeneous enhancement after injection of gadolinium and an enlarged infundibulum with a maximum diameter of 8 mm. As a venous sampling of the inferior petrosal sinus after 10 µg iv desmopressin stimulation revealed a central to peripheral ACTH ratio consistent with a pituitary ACTH-secreting tumor, transphenoidal explorative surgery was performed and a 4-mm pituitary adenoma immunopositive for ACTH was disclosed and removed. Since postoperative hormonal evaluation showed persistent hypercortisolism, confirmed by dynamic tests, the patient again underwent surgery by transcranial access and the infundibulum mass was removed. Histology and immunochemistry were consistent with an ACTH-secreting adenoma. A few months after the second operation, cushingoid features were significantly reverted and symptoms improved. CONCLUSION: Although Cushing's patients bearing multiple adenomas have already been documented, the presence of two adenomas both immunohistochemically positive for ACTH is a very rare cause of Cushing's disease and this is the first report of a case of double ACTH-producing adenomas, one located in the pituitary gland and one attached to the stalk.

Adjuvant temozolomide chemotherapy for treatment of papillary tumor of the pineal region.

BACKGROUND: We present a personal case of papillary pineocytoma in a 42-year-old woman. METHODS: The lesion was first treated surgically both for diagnostic aims and for resolution of the mass effect causing hydrocephalus and correlated neurological disturbances. Because the tumor recurred after surgery and radiotherapy, we decided to further treat the patient with chemotherapy, in particular with temozolomide. RESULTS: Currently, almost 9 years after the first treatment, the patient is symptom-free and follow-up magnetic resonance imaging shows no tumor recurrence. CONCLUSION: Although surgery should be considered the first-choice therapy, we think that temozolomide can be a valid option in case of recurrence of these rare tumors.

Differential signature of the centrosomal MARK4 isoforms in glioma.

BACKGROUND: MAP/microtubule affinity-regulating kinase 4 (MARK4) is a serine-threonine kinase expressed in two spliced isoforms, MARK4L and MARK4S, of which MARK4L is a candidate for a role in neoplastic transformation. METHODS: We performed mutation analysis to identify sequence alterations possibly affecting MARK4 expression. We then investigated the MARK4L and MARK4S expression profile in 21 glioma cell lines and 36 tissues of different malignancy grades, glioblastoma-derived cancer stem cells (GBM CSCs) and mouse neural stem cells (NSCs) by real-time PCR, immunoblotting and immunohistochemistry. We also analyzed the sub-cellular localisation of MARK4 isoforms in glioma and normal cell lines by immunofluorescence. RESULTS: Mutation analysis rules out sequence variations as the cause of the altered MARK4 expression in glioma. Expression profiling confirms that MARK4L is the predominant isoform, whereas MARK4S levels are significantly decreased in comparison and show an inverse correlation with tumour grade. A high MARK4L/MARK4S ratio also characterizes undifferentiated cells, such as GBM CSCs and NSCs. Accordingly, only MARK4L is expressed in brain neurogenic regions. Moreover, while both MARK4 isoforms are localised to the centrosome and midbody in glioma and normal cells, the L isoform exhibits an additional nucleolar localisation in tumour cells. CONCLUSIONS: The observed switch towards MARK4L suggests that the balance between the MARK4 isoforms is carefully guarded during neural differentiation but may be subverted in gliomagenesis. Moreover, the MARK4L nucleolar localisation in tumour cells features this MARK4 isoform as a nucleolus-associated tumour marker.

Sudden cardiac death in a young HIV-positive man on effective antiretroviral therapy.

We describe the case of a young HIV-positive man on effective HAART with excellent viro-immunological control who presented a massive cardiac infarction. Despite the presence of clinical risk factors for cardiovascular disease, the patient had normal arterial carotid IMT values, known to be strong predictors of atherosclerosis and stroke. Interestingly, parameters of T-cell activation (CD8+CD38+) were shown to increase just before the onset of myocardial infarction. As T-cell activation is known to mediate atherosclerosis, the authors suggest that surrogate immunologic markers should be identified to better assess cardiovascular risk in the setting of HIV infection.