Needs of neuro-oncological patients and their caregivers during the hospitalization and after discharge: results from a longitudinal study.

PURPOSE: The aims of this study are to identify neuro-oncological patients' and their caregivers' needs during hospitalization (T0) and at 4 months after discharge (T1); to analyze the longitudinal changes in patients' and caregivers' needs and burden; to identify correlations between patients' needs and caregivers' burden and needs. METHODS: A pilot observational longitudinal study was conducted on 94 neuro-oncological patients and their caregivers using NEQ to evaluate patients' needs, CNA, and FSQ for caregivers' needs and burden at T0 and T1. Descriptive statistics were performed to illustrate the distribution of questionnaires' scores. The longitudinal change of NEQ, FSQ, and CNA scores were investigated using Wilcoxon test. Spearman's correlation was used to measure the relation between NEQ and FSQ and CNA scores. RESULTS: The most frequent patients and caregivers' needs were material and informative. Needs tend to decrease over time; in particular FSQ factor "need for knowledge about the disease", CNA factor "Information/communication needs" and CNA total score significantly decreased (p < 0.001). NEQ total score significantly correlated with FSQ factors "emotional burden" and "need for knowledge about the disease" and CNA total and factors scores at T0 and T1. At T0, NEQ correlated significantly with FSQ factor "thoughts about death", while at T1, it correlated with FSQ factor "problems in social involvement". CONCLUSIONS: It is crucial to plan an assessment of patients' and caregivers' needs from the very beginning, in order to identify those individuals potentially at risk of developing high level of distress and to provide information and support following the illness trajectory of the brain tumor.

A case of medulloblastoma in adult patient affected by anaplastic oligoastrocytoma.

Medulloblastomas and high-grade gliomas (HGG) are two distinct brain tumor, with different peculiarities in terms of age of onset, localizations and prognosis. The coexistence of the two neoplasms in the same adult patient is an extremely rare event. We present the case of a woman treated with radio-chemotherapy for an HGG, who developed a cerebellar medulloblastoma 7 years later. Considering the poor prognosis of these tumors, the lack of knowledge about the mechanisms of onset as well as effective therapies, it is necessary to determine the exact role of irradiation and the presence of any potential molecular genetic abnormalities in the developing of the two tumors.

Biomarkers of Tolerance in Kidney Transplantation: Are We Predicting Tolerance or Response to Immunosuppressive Treatment?

We and others have previously described signatures of tolerance in kidney transplantation showing the differential expression of B cell-related genes and the relative expansions of B cell subsets. However, in all of these studies, the index group-namely, the tolerant recipients-were not receiving immunosuppression (IS) treatment, unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS-independent signature of tolerance. Analyzing gene expression in three independent kidney transplant patient cohorts (232 recipients and 14 tolerant patients), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B cells. We have defined and validated a new gene expression signature that is independent of drug effects and also differentiates tolerant patients from healthy controls (cross-validated area under the receiver operating characteristic curve [AUC] = 0.81). In a prospective cohort, we have demonstrated that the new signature remained stable before and after steroid withdrawal. In addition, we report on a validated and highly accurate gene expression signature that can be reliably used to identify patients suitable for IS reduction (approximately 12% of stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS minimization safe and hence allow critical improvements in kidney posttransplant management.

Safety and efficacy of primary central nervous system lymphoma treatment in elderly population.

Elderly patients represent an important subgroup in primary central nervous system lymphoma (PCNSL) that accounts for approximately half the cases. Furthermore age represents one of the heaviest prognostic factors and in some cases it has more effect on survival than therapies. We performed a retrospective analysis to assess the toxicity and the efficacy of high-dose methotrexate (HDMTX) chemotherapy in a PCNSL population older than 70 years. Seventeen consecutive immunocompetent patients older than 70 years, with histologically confirmed PCNSL, without systemic involvement, treated with HDMTX at our institution between May 2005 and April 2013, were retrospectively evaluated. Main outcome measures were acute toxicity and tumour response. No evidence of haematological toxicity was recorded in 47 % of patients and no deaths related to toxicity grade were reported. Patients achieved a partial response after 3 cycles of chemotherapy in 53 % of cases. The median overall survival (m-OS) from diagnosis was 20.9 months (range 5.2-34 months), with OS-12 of 58.8 % and an OS-24 of 45.4 %. Since there is no standard of care in the treatment of PCNSL in elderly population, it should be taken into account that elderly patients not always can be considered "fragile" and the general tendency to less treat to avoid severe toxicity should not be the rule.

Clinical management of grade III oligodendroglioma.

Oligodendrogliomas represent the third most common type of glioma, comprising 4%-15% of all gliomas and can be classified by degree of malignancy into grade II and grade III, according to WHO classification. Only 30% of oligodendroglial tumors have anaplastic characteristics. Anaplastic oligodendroglioma (AO) is often localized as a single lesion in the white matter and in the cortex, rarely in brainstem or spinal cord. The management of AO is deeply changed in the recent years. Maximal safe surgical resection followed by radiotherapy (RT) was considered as the standard of care since paramount findings regarding molecular aspects, in particular co-deletion of the short arm of chromosome 1 and the long arm of chromosome 19, revealed that these subsets of AO, benefit in terms of overall survival (OS) and progression-free survival (PFS), from the addition of chemotherapy to RT. Allelic losses of chromosomes 1p and 19q occur in 50%-70% of both low-grade and anaplastic tumors, representing a strong prognostic factor and a powerful predictor of prolonged survival. Several other molecular markers have potential clinical significance as IDH1 mutations, confirming the strong prognostic role for OS. Malignant brain tumors negatively impacts on patients' quality of life. Seizures, visual impairment, headache, and cognitive disorders can be present. Moreover, chemotherapy and RT have important side effects. For these reasons, "health-related quality of life" is becoming a topic of growing interest, investigating on physical, mental, emotional, and social well-being. Understanding the impact of medical treatment on health-related quality of life will probably have a growing effect both on health care strategies and on patients.

Cognitive strategies and quality of life of patients with high-grade glioma.

The purpose of this study was to analyze the psychological well-being, quality of life, and cognitive strategies activated by patients with high-grade glioma. We hypothesized that the self-perceived quality of life is modulated by physical and psychological factors and that in order to understand this modulation more psychometric approaches are necessary. Data were collected from a sample of 73 consecutive patients with a histological diagnosis of primary malignant brain cancer (grade IV glioblastoma and grade III anaplastic astrocytoma) hospitalized in a specialized Italian center. The Functional Assessment of Cancer Therapy (FACT) scale and the Schedule of Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW) scale were used to assess quality of life. The mean FACT-Brain (Br) score was 122.37. Similarly, the median SEIQoL-DW score was 72.9 out of a maximum value of 100. No gender effect was found in relation to overall quality of life. Patients with high depression and/or anxiety scores reported lower quality of life (QoL) scores in all the instruments considered. We did not find any gender effect concerning depression and anxiety levels. However, we found that men and women, though having similar physical and functional well-being, reported different QoL determinants, since men seem to rely more on physical adjustment, while women activate more introspective strategies. Positive actions, family issues, negative thoughts, health, and positive thoughts were found to be the most reported themes. In conclusion, the present study strongly suggests that a positive psychological adjustment is possible also in the event of a severe diagnosis and during aggressive treatments, but QoL determinants might be considered too in order to help health professionals to understand patients' experience and to meet their needs.

Update on treatment strategies for anaplastic glioma: a review of literature.

Anaplastic gliomas (AG) include 6-10% of all newly diagnoses of primary brain tumors. They have an unfavourable prognosis and, to date, there is not an established treatment universally recognized. Four recent randomized clinical trials were identified for a total of 1,170 patients (anaplastic-astrocytomas, anaplasticoligoastrocytoma, anaplastic-oligodendroglioma), in order to define the better sequence and timing of chemo-radiotherapy, Three studies compared radiotherapy (RT) treatment vs. radio-chemotherapy with procarbazine-lomustine-vincristine (PCV) or temozolomide (TMZ) or dibromodulcitol and bichloroethylnitrosurea (DBD/BCNU) and only one compared RT vs chemotherapy (CT) with PCV or TMZ. Results show no significant differences in terms of PFS/OS between RT/CT alone or combined treatment although a trend toward an improvement of OS was observed after RT + CT treatment (m-OS in RT + adjuvant PCV was 42.3 vs. 30.6 months in RT alone p=0.0003). Grade 3-4 mielotoxicity has been observed in almost all cases of patients treated with PCV + RT. None of four studies reviewed conducted a head to head comparison between PCV vs. TMZ. Only a study randomized patients to PCV/TMZ without however providing data in terms of PSF and OS between the two treatments. It found no significant differences in PFS from initial RT and adjuvant CT (PCV-TMZ) at progression compared to initial CT followed by RT at progression. The optimal treatment of AG should reasonably consider not only the histology as well as the molecular markers of the tumor, but also clinical conditions, age of patients, life expectancy, Karnofsky-performance-status and tumor resection to achieve in future the personalization of care.

Safety of bevacizumab in patients with malignant gliomas: a systematic review.

Angiogenesis has recently become a major target for the development of new antineoplastic drugs. The most serious adverse events linked to angiogenesis inhibitors are venous or arterial thromboembolism and haemorrhage. Thus, there is need to define with more certainty the impact of these new drugs in terms of adverse effects in neurological patients. The aim of the study is to assess the risk of venous thromboembolism (VTE) and bleeding in patients with malignant gliomas treated with bevacizumab with or without concomitant anticoagulant therapy. A review of published literature was performed in Medline, from which 476 records were identified. A total of 27 full-text articles, including retrospective analyses, retrospective reviews, and open label trials, were assessed for eligibility. The investigated drugs included bevacizumab alone, bevacizumab plus chemotherapy with/without concomitant radiation therapy; only two articles dealt with bevacizumab in association with anticoagulant treatment. A total of 2,208 patients with malignant gliomas, were identified and included in the analysis. From data it appears that patients receiving bevacizumab had a major risk of developing VTE that increased when bevacizumab is associated with radio-chemotherapy (4.27 vs 7.46 %). Regarding bleeding, data showed that patients treated with anticoagulant had a significantly increased risk of severe central nervous system (CNS) bleeding compared to patients not receiving anticoagulant therapy (0.6 vs 8.2 %). The use of bevacizumab combined with chemo-radiotherapy seems to be associated with a higher risk for VTE compared to patients receiving antiangiogenic therapy alone. The associated use of anticoagulants and bevacizumab far increases the risk of developing CNS and non-CNS bleeding higher than grade 3, compared to patients receiving bevacizumab alone.

Liposomal cytarabine in neoplastic meningitis from primary brain tumors: a single institutional experience.

Neoplastic meningitis (NM) is diagnosed in 1-2 % of patients with primary brain tumors. Standard treatment of NM includes single-agent or combination chemotherapy, with compounds such as methotrexate, thiotepa, and cytarabine (Ara-C) or its injectable, sustained-release formulation Depocyte(®). In this Report, we reported the data of efficacy and tolerability of an intrathecal Depocyte(®) regimen for patients presenting with NM from primary brain tumors. We described 12 patients with NM confirmed at magnetic resonance imaging (MRI) and with a positive cerebrospinal fluid (CSF) cytology. Patients were treated with repeated courses of intrathecal Depocyte(®) (once every 2 weeks for 1 month of induction therapy and as consolidation therapy on a monthly base in responding patients). Twelve patients (10 males and 2 females) were treated by our Institution. The diagnosis of primitive brain tumor was medulloblastoma in six patients, germinoma in two patients, pylocitic astrocytomas with spongioblastic aspects, teratocarcinoma, meningeal melanoma, and ependimoma in the other four patients. The total number of Depocyte(®) cycles ranged from one to nine. In 7/12 patients, there was clinical and/or radiological response after Depocyte(®), and the toxicity was moderate and transient, mainly due to the lumbar puncture procedure. In the two patients with germinoma, we observed a normalization of MRI Imaging and negativization of CSF with disappearance of the tumor cells. OS was 180 days (range 20-300, CI 95 %).

Adult medulloblastoma: multiagent chemotherapy with cisplatinum and etoposide: a single institutional experience.

In 1991, a prospective phase II trial was initiated to evaluate the efficacy of treatment for adults with medulloblastoma (MB). After surgery, patients were staged with a neuroradiologic examination of the brain and neuroaxis and by cerebrospinal fluid cytology. All patients received three cycles of upfront cisplatinum (cisplatinum) and etoposide (VP16) chemotherapy followed by cranio-spinal radiation therapy. The current article reports on the long-term results from that trial. After a median follow-up of 14.9 years, among a total of 28 adults with MB, the overall progression-free survival and overall survival (OS) rates at 5 years were 57.6 and 80%, respectively. The median OS for the whole group of patients was 11.3 years. The observed toxicity was mainly hematological, with leukopenia and thrombocytopenia (16% of grades 3 and 4). In summary, in our small series of patients, the role of combination administration of CDDP + VP16 started before the initiation of radiotherapy in reducing recurrences, particularly distant recurrences, remains unclear. To know whether adding chemotherapy to craniospinal radiation in adult therapy increases relapse-free and overall survival, we must await the results of a larger randomized controlled clinical trial.

Rechallenge with temozolomide in recurrent glioma.

Despite a confirmed survival benefit associated with adjuvant radio- and chemotherapy, the majority of patients with malignant glioma relapse after initial therapy. Recurrent malignant glioma treatment has not been standardised and usually the response rate to standard chemotherapy protocols for recurrent malignant glioma is less than 30%. The growing body of evidence demonstrating the clinical importance of O6-methylguanine methyltransferase (MGMT) has generated a considerable interest in the exploration of strategies to overcome MGMT-mediated resistance to alkylating agents; for example protracted administration of Temozolomide (TMZ) may result in more extensive and sustained depletion of MGMT; for this reason a variety of dosing schedules that increase the duration of exposure and the cumulative dose of TMZ are being investigated for the treatment of patient with recurrent malignant glioma after standard treatment. The most widely studied regimens in this setting include (1) 21 of 28-day schedule at a dose of 75-100 mg/m(2)/day; (2) 7 of 14-day schedule at a dose of 150 mg/m(2)/day, also referred to as the ''one week on/one week off'' schedule; (3) Continuous daily schedule at a dose of 50 mg/m(2)/day. An alternative dosing schedule of TMZ may be a reasonable option in patients having high-grade gliomas with recurrence after standard therapy.

Lecture: fotemustine in brain tumors.

Fotemustine (FTMS) is a third-generation nitrosourea, in preclinical studies, FTMS compared favorably with carmustine (BCNU) and lomustine (CCNU) against several human tumor cell lines. In conventional schedule, FTMS is administered at a dose of 100 mg/sqm/week for three consecutive weeks as induction (I) treatment, followed by 100 mg/sqm every three weeks, after a 5-week rest, as maintenance (M). Several Italian groups reported the results using FTMS in malignant glioma patients recurring after temozolomide standard treatment. In these papers, the 6-progression free survival are ranging from 20 to 52%. With the schedule (I + M) myelosuppression is observed in more than 30% of patients, and thrombocytopenia and leukopenia are more frequent and significant in Temozolomide pretreated patients. On the bases of the hematological toxicities several authors experimented new schedules of FTMS administrated at low doses. Recently, some authors reported the interesting results of a multicenter study on recurrent glioblastoma multiforme patients combining FTMS with new antiangiogentic agent bevacizumab.

Infections in neuro-oncology.

Infections represent a serious and frequent complication in neuro-oncology patients. Decreased immune defences, along with poor nutritional status are the main predisposition factors. The combined therapeutic strategies of chemotherapy and radiotherapy may favour bone marrow depression and further increase the risk of developing opportunistic infections in brain tumour patients. The spectrum of infections in neuro-oncology patients is large and includes opportunistic infections by bacteria, viruses, fungi and parasites. Importantly, a high index of suspicion for opportunistic infections in general should be maintained, especially in glioma patients receiving dose-dense schedules of temozolomide. After neurosurgical procedures, infections most commonly present as meningitis, subdural empyema, or cerebral abscess. Infections represent a frequent and possibly serious complication in general immunocompromised oncology population. It should be underlined that infections are not limited to immunocompromised patients, being also present at the early disease stages, especially due to therapeutic strategies (chemo and radiotherapy, surgical procedures). Therefore this issue deserves more attention in neuroncology setting.

Privacy-solidarity conflict: the communication with the support group.

Actually guidelines require that patient must be informed about his condition so that he can choose the persons he wants to share these information with. Nonetheless, the caregiver usually gets an intermediary role in doctor-patient communication thus becoming the doctor's main conversation partner and claiming to be given more information than the patient himself. A more complex situation is about brain tumours patients sometimes affected by cognitive deficiencies, compromising their comprehension skills or their capability of keeping the information they are being given. A preliminary study allowed to submit separately to brain tumour patients and their family members a semi-structured interview. Although doctors communicate diagnosis and therapeutic plans, patients and their family members often do not seem to remember the information they are given. An important percentage of patients and their carers cannot tell correctly what they was said by the doctors. Only a minor percentage of patients do not want to know all details of their disease. Instead, most of the family members, would rather their beloved were given just partial information on their conditions or even not given information at all. Communication with patients and their carers requires careful re-negotiation in a multiple time-points, rather than a one-off communication episode.

Neuro-oncological diagnosis in patients without histological confirmation.

The impossibility to conduct a histological diagnosis could be due to different reasons: (1) patient's refusal to undergo surgery/biopsy. (2) Technical difficulties: despite the advance in surgical procedures, the removal of lesions that are located either in critical or in deep areas represents a considerable risk for patients. (3) Quality/quantity of the sample. In rare cases even when the surgical sample is achieved it could be impossible to reach a histological confirmation, for example due to the small amount of tissue obtained. The lack of histology leads to suboptimal therapy, incorrect prognosis, and misinterpretation of clinical trials and furthermore undermines the possibility to perform most radiation and chemotherapy protocols. In this setting the morphological data obtained with conventional MR imaging may be integrated with the metabolic, structural and perfusional information provided by new MR and metabolic techniques (spectroscopy, SPECT, PET in particular).

Malignant gliomas: early diagnosis and clinical aspects.

Brain tumor symptoms vary greatly from person to person because of two factors: location and size of tumors. The size of a tumor, however, does not necessarily affect the severity of symptoms. Manifestations depend on the cause of the symptoms: an increase in ICP, direct compression of gray or white matter, shifting of intracranial contents, or secondary cerebral ischemia. Symptoms may be non-specific and include headache, altered mental status, ataxia, nausea, vomiting, weakness, and gait disturbance. Left-sided weakness may be seen in a patient with a tumor pressing on the contra-lateral motor strip or speech difficulties may occur if a tumor is in the dominant hemisphere. Up to a third of people report having seizures prior to being diagnosed with a brain tumor. Rarely, brain tumor can present with psychiatric symptoms but without other neurological signs or symptoms. Evaluation for brain tumor is indicated in any patient with chronic, persistent headache associated with protracted nausea, vomiting, seizures, changes in headache pattern, neurologic symptoms, and change in personality.

Metabolic, electrolytes disorders and tromboembolic risk in malignant glioma patients.

In malignant gliomas, the management of symptoms and minimization of side effects assume major importance. Corticosteroids provide transient relief from neurological symptoms. However, treatment with steroids is also commonly associated with considerable side-effects including: hyperglycemia, osteoporosis, myopathy, lymphopenia and others. Sometimes, antiepileptic drugs may contribute to clinical decline of neuro-oncological patients in stable disease not only by neuropsychological impairment but also by metabolic interations. Several studies have demonstrated a high frequency of hyponatremia among patients treated with carbamazepine and particularly with oxacarbamazepine. Venous thromboembolism is a common complication in patients with cancer and it is particularly high in malignant gliomas, occurring in approximately 20-30% of such patients. Prophylactic treatment in patients with glioblastoma is a key topic. The role of prophylaxis has not yet been established with certainty. Overall the data show a clear reduction of venous thromboembolic events in patients treated with intermittent pneumatic compression (IPC). The addition of enoxaparin dose of 6.000 UI, starting in the perioperative period, induces an increase of major bleeding events. In the absence of availability of IPC, the use of enoxaparin 4.000 UI in addition to graduated compression stockings, reduces thromboembolic events without major bleeding events.

Consent and awareness: mental conditions at diagnosis.

Informed consent is often talked about in an abstract manner, as if consent and information necessarily have to go together, and almost as if consent is "naturally" the quintessence of a good professional relationship in modern medicine. The United States is considered as the place of origin of informed consent. In Italy the concept of informed consent can be found for the first time in the 1990s. Informed consent is based on the principles of autonomy and benefit, on awareness and information. Already at the moment of the diagnosis, in addition to motor deficits, focal cognitive deficits are often present. It is important for the doctor to consider and evaluate the actual ability to comprehend and process the clinical situation on the part of the patient. At the Neuro-Oncology Division of the Carlo Besta Neurological Institute of Milan, we sought to analyse how and to what extent the brain tumour alters and conditions cognitive functionality, and hence the ability to process, comprehend and retain information during a diagnostic communication, and whether and how this moment is influenced by the presence of any global or specific cognitive deficits. Preliminary and performed on a numerically limited sample, 30 patients out of 42, in a specific neuropsychological survey, display cognitive attention and memory deficits despite achieving an adequate score on a global cognitive assessment. The physician's attention to the cognitive faculties of a patient to whom a pathological condition and a therapeutic approach are being presented is fundamental.

Natural history and management of brainstem gliomas in adults. A retrospective Italian study.

Brainstem gliomas in adults are rare tumors, with heterogeneous clinical course; only a few studies in the MRI era describe the features in consistent groups of patients. In this retrospective study, we report clinical features at onset, imaging characteristics and subsequent course in a group of 34 adult patients with either histologically proven or clinico-radiologically diagnosed brainstem gliomas followed at two centers in Northern Italy. Of the patients 18 were male, 14 female, with a median age of 31. In 21 of the patients histology was obtained and in 20 it was informative (2 pilocytic astrocytoma, 9 low-grade astrocytoma, 8 anaplastic astrocytoma and 1 glioblastoma). Contrast enhancement at MRI was present in 14 patients. In all of the 9 patients who were investigated with MR spectroscopy, the Cho/NAA ratio was elevated at diagnosis. In 8 of the patients, an initial watch and wait policy was adopted, while 24 were treated shortly after diagnosis with either radiotherapy alone [4] or radiotherapy and chemotherapy [20] (mostly temozolomide). Only minor radiological responses were observed after treatments; in a significant proportion of patients (9 out of 15) clinical improvement during therapy occurred in the context of radiologically (MRI) stable disease. Grade III or IV myelotoxicity was observed in 6 patients. After a follow-up ranging from 9 to 180 months, all but 2 patients have progressed and 14 have died (12 for disease progression, 2 for pulmonary embolism). Median overall survival time was of 59 months. Investigation of putative prognostically relevant parameters showed that a short time between disease onset and diagnosis was related to a shorter survival. Compared with literature data, our study confirms the clinical and radiological heterogeneity of adult brainstem gliomas and underscores the need for multicenter trials in order to assess the efficacy of treatments in these tumors.