First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia.

BACKGROUND: Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking. METHODS: In a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, <10-4 [i.e., <1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival. RESULTS: A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P<0.001 for both comparisons), but it was not significantly higher in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P = 0.32). Three-year progression-free survival was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P<0.001). Progression-free survival at 3 years was also higher with venetoclax-obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P<0.001), but not with venetoclax-rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P = 0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%). CONCLUSIONS: Venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. (Funded by AbbVie and others; GAIA-CLL13 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.).

The effect of a palliative care pathway on medical interventions at the end of life: a pre-post-implementation study.

PURPOSE: Adequate integration of palliative care in oncological care can improve the quality of life in patients with advanced cancer. Whether such integration affects the use of diagnostic procedures and medical interventions has not been studied extensively. We investigated the effect of the implementation of a standardized palliative care pathway in a hospital on the use of diagnostic procedures, anticancer treatment, and other medical interventions in patients with incurable cancer at the end of their life. METHODS: In a pre- and post-intervention study, data were collected concerning adult patients with cancer who died between February 2014 and February 2015 (pre-PCP period) or between November 2015 and November 2016 (post-PCP period). We collected information on diagnostic procedures, anticancer treatments, and other medical interventions during the last 3 months of life. RESULTS: We included 424 patients in the pre-PCP period and 426 in the post-PCP period. No differences in percentage of laboratory tests (85% vs 85%, p = 0.795) and radiological procedures (85% vs 82%, p = 0.246) were found between both groups. The percentage of patients who received anticancer treatment or other medical interventions was lower in the post-PCP period (40% vs 22%, p < 0.001; and 42% vs 29%, p < 0.001, respectively). CONCLUSIONS: Implementation of a PCP resulted in fewer medical interventions, including anticancer treatments, in the last 3 months of life. Implementation of the PCP may have created awareness among physicians of patients' impending death, thereby supporting caregivers and patients to make appropriate decisions about medical treatment at the end of life. TRIAL REGISTRATION NUMBER: Netherlands Trial Register; clinical trial number: NL 4400 (NTR4597); date registrated: 2014-04-27.

Hospitalisations of patients with cancer in the last stage of life. Reason to improve advance care planning?

OBJECTIVE: The aim of this study is to examine why patients are hospitalised in the last stage of life. METHODS: Our study was conducted in a large Dutch teaching hospital. We conducted a retrospective chart review of patients aged ≥18 years who died of cancer either during hospitalisation or after discharge to receive terminal care outside the hospital. We collected data about the characteristics of these hospitalisations and indicators of advance care planning. RESULTS: Of the 264 deceased patients, 56% had died in the hospital and 44% after hospital discharge. Of all patients, 80% had been admitted to the hospital because of symptom distress. Dyspnoea (39%) and pain (33%) were the most common symptoms. Most patients underwent diagnostic procedures (laboratory tests [97%] and radiology tests [91%]) and received medical treatment (analgesics [71%] and antibiotics [55%]) during their hospitalisation. A 'Do-Not-Resuscitate' code had been recorded before admission in 42% of the patients and in an additional 52% during admission. CONCLUSION: Our study shows that patients with cancer in the last stage of life were mainly admitted to the hospital because of symptom distress. Some hospitalisations and in-hospitals deaths may be avoided by more timely recognition of patients' impending death and start of advance care planning.

Quality of hospital discharge letters for patients at the end of life: A retrospective medical record review.

OBJECTIVE: For patients who are discharged to go home after a hospitalisation, timely and adequately informing their general practitioner is important for continuity of care, especially at the end of life. We studied the quality of the hospital discharge letter for patients who were hospitalised in their last year of life. METHODS: A retrospective medical record review was performed. Included patients had been admitted to the hospital during the period 1 January to 1 July 2017 and had died within a year after discharge. RESULTS: Data were collected from records of 108 patients with cancer or other diseases. For 57 patients (53%), the discharge letter included information that related to their limited life expectancy (e.g., agreements about treatment limitations), whereas the patient's limited life expectancy was addressed in the medical record in 76 cases (70%). We found related information in discharge letters for 36 patients (66%) who died <3 months compared to 21 patients (40%) who died 3-12 months after hospitalisation (p < 0.01). CONCLUSION: For patients with a limited life expectancy going home after a hospitalisation, one out of two hospital discharge letters lacked any information addressing their limited life expectancy. Specific guidelines for medical information exchange between care settings are needed.

Effects of Implementation of a Standardized Palliative Care Pathway for Patients with Advanced Cancer in a Hospital: A Prospective Pre- and Postintervention Study.

CONTEXT: Early integration of oncology and palliative care has been recommended to improve patient outcomes at the end of life. A standardized Palliative Care Pathway, consisting of a structured electronic medical checklist, may support such integration. OBJECTIVES: We studied the effect of implementation of a Palliative Care Pathway on patients' place of death and advance care planning. METHODS: We conducted a prospective pre- and postimplementation study of adult patients with cancer from a single hospital who died between February 2014 and February 2015 (pre-implementation period) or between November 2015 and November 2016 (post-implementation period). RESULTS: We included 424 patients in the pre- and 426 in the post-implementation period. The pathway was started for 236 patients (55%) in the post-implementation period, on average 33 days (IQR 12-73 days) before death. 74% and 77% of the patients died outside hospital in the pre- and post-implementation period, respectively (P = 0.360). When the PCP was initiated, 83% died outside hospital. Bad-news conversations (75% and 62%, P < 0.001) and preferred place of death (47% and 32%, P < 0.001) were more often documented in the pre-implementation period, whereas a DNR-code was more often documented during the post-implementation period (79% and 89%, P < 0.001). CONCLUSIONS: Implementation of a Palliative Care Pathway had no overall positive effect on place of death and several aspects of advance care planning. Start of a Palliative Care Pathway in the last months of life may be too late to improve end-of-life care. Future research should focus on strategies enabling earlier start of palliative care interventions.

Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis.

PURPOSE: To evaluate the efficacy and safety of a slow-release formulation of cytarabine (DepoCyt; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) that maintains cytotoxic concentrations of cytarabine (ara-C) in the CSF of most patients for more than 14 days. PATIENTS AND METHODS: Twenty-eight patients with lymphoma and a positive CSF cytology were randomized to receive DepoCyt 50 mg once every 2 weeks or free ara-C 50 mg twice a week for 1 month. Patients whose CSF cytology converted to negative and who did not have neurologic progression received an additional 3 months of consolidation therapy and then 4 months of maintenance therapy. All patients received dexamethasone 4 mg orally bid on days 1 through 5 of each 2-week cycle. RESULTS: The response rate was 71% for DepoCyt and 15% for ara-C on an intent-to-treat basis (P =.006). All of the patients on the DepoCyt arm but only 53% of those on the ara-C arm were able to complete the planned 1-month induction therapy regimen. Time to neurologic progression and survival trend in favor of DepoCyt (median, 78.5 v 42 days and 99.5 v 63 days, respectively; P >.05). DepoCyt treatment was associated with an improved mean change in Karnofsky performance score at the end of induction (P =.041). The major adverse events on both arms were headache and arachnoiditis, which were often caused by the underlying disease. CONCLUSION: DepoCyt injected once every 2 weeks produced a high response rate and a better quality of life as measured by Karnofsky score relative to that produced by free ara-C injected twice a week.

Two primary brain tumors in one child.

We studied a 4-year-old boy with symptoms and signs of a posterior fossa tumor. CT showed two separate intracranial tumors: a fourth ventricle choroid plexus papilloma and a frontal subependymal giant-cell astrocytoma. This case emphasizes that, even in the absence of special genetic predisposition to CNS tumors, two separate intracranial masses may not represent CSF metastasis of a single primary tumor.

Brain tumors in children and adolescents--III. Effects of radiation and hormone status on intelligence and on working, associative and serial-order memory.

The effects on intelligence and memory of two post-surgical conditions (radiation treatment, hormone deficiency and supplementation) were explored in 46 children and adolescents with tumors in a variety of brain sites. Verbal intelligence, but not non-verbal intelligence, varied positively with age at radiation treatment. Memory for word meanings was unrelated to either radiation history or to hormone status. Severe deficits in serial position memory occurred with impaired hormone function and an older age at tumor onset. Severe deficits in working memory were associated with a history of radiation and a principal tumor site that involved thalamic/epithalamic brain regions. Radiation treatment and hormone status affect later cognitive function in children and adolescents with brain tumors. Although the greater vulnerability of the verbal intelligence of the younger radiated child and the serial order memory of the child with later tumor onset and hormone disturbances remain to be explained, and although the form of the relationship between radiation and tumor site is not fully understood, the data highlight the need to consider the cognitive consequences of pediatric brain tumors according to a set of markers that include maturational rate, hormone status, radiation history, and principal site of the tumor.

Ependymoma: results, prognostic factors and treatment recommendations.

PURPOSE: To review the University of Florida experience in treating ependymomas, analyze prognostic factors, and provide treatment recommendations. METHODS AND MATERIALS: Forty-one patients with ependymoma and no metastases outside the central nervous system received postoperative radiotherapy with curative intent between 1966 and 1989. Ten patients had supratentorial lesions, 22 had infratentorial lesions, and 9 had spinal cord lesions. All patients had surgery (stereotactic biopsy, subtotal resection, or gross total resection). Most patients with high-grade lesions received radiotherapy to the craniospinal axis. Low-grade intracranial lesions received more limited treatment. Spinal cord lesions were treated using either partial spine or whole spine fields. RESULTS: Of 32 intracranial tumors, 21 recurred, all at the primary site; no spinal cord tumors recurred. Overall 10-year survival rates were 51% (absolute) and 46% (relapse-free); by tumor site: spinal cord, 100%; infratentorial, 45%; supratentorial, 20% (p = 0.002). On multivariate analysis, tumor site was the only factor that influenced absolute survival (p = 0.0004); other factors evaluated included grade, gender, age, duration of symptoms, resection extent, primary tumor dose, treatment field extent, surgery-to-radiotherapy interval, and days under radiotherapy treatment. CONCLUSIONS: Patients with supratentorial or infratentorial tumors receive irradiation, regardless of grade. Craniospinal-axis fields are used when spinal seeding is radiographically or pathologically evident. Spinal cord tumors are treated using localized fields to the primary site if not completely resected. Failure to control disease at the primary site remains the main impediment to cure.

Medulloblastoma: time-dose relationship based on a 30-year review.

PURPOSE: Time-dose relationships have proven important in many cancer sites. This study evaluates the time factors involved in the successful postoperative radiotherapy of medulloblastoma, based on a 30-year experience in a single institution. METHODS AND MATERIALS: Fifty-three patients with medulloblastoma received postoperative craniospinal radiotherapy with curative intent between 1963 and 1993. Seven patients (13%) underwent biopsy alone, 28 patients (53%) had subtotal excision, and 18 patients (34%) had gross total excision. Eleven patients received adjuvant chemotherapy. The mean posterior fossa dose was 53.1 Gy; most patients received 54.0 Gy (range, 34.3 to 69.6 Gy). For 41 patients receiving once-a-day therapy, the mean dose was 50.6 Gy (range, 34.3 to 56.0 Gy). For 12 patients receiving twice-a-day therapy, the mean dose was 61.8 Gy (range, 52.6 to 69.6 Gy). Minimum follow-up was 2 years, and median follow-up was 10.7 years. Survival, freedom from relapse, and disease control in the posterior fossa were calculated using the Kaplan-Meier method, and multivariate analysis was performed for prognostic factors. Variables related to radiotherapy were examined, including dose to the craniospinal axis, dose to the posterior fossa, fractionation (once-a-day vs. twice-a-day), use of adjuvant chemotherapy, risk group [high (> or =T3b or > or =M1) or low (< or =T3a and M0-MX)], interval between surgery and radiotherapy (excluding patients receiving chemotherapy before radiotherapy), and duration of radiotherapy. RESULTS: At 5 and 10 years, overall survival rates were 68 and 64%, respectively, and freedom-from-relapse rates were 61 and 52%, respectively. Rates of disease control in the posterior fossa at 5 and 10 years were 79 and 68%, respectively. At 5 years, absolute survival rates after biopsy alone, subtotal excision, and gross total excision were 43, 67, and 78%, respectively (p=0.04), and posterior fossa control rates were 27, 89, and 83%, respectively (p=0.004). Duration of the treatment course was the only radiotherapy-related variable with a significant impact on freedom from relapse and posterior fossa control. For patients whose radiation treatment duration was < or =45 days, posterior fossa control was 89% at 5 years, compared with 68% for those treated for >45 days (p=0.01). Duration of treatment also affected freedom from relapse at 5 years: < or =45 days (76%) compared with >45 days (43%), p=0.004. CONCLUSION: Our study demonstrates that if adequate doses are used, then radiotherapy treatment duration will significantly affect the outcome in terms of control of disease in the posterior fossa and freedom from relapse. Fractions of at least 1.75 Gy given once a day, or a twice-a-day regimen should yield optimal local control results.

Identification of marker chromosomes in a human medulloblastoma cell line (D283 Med).

The human medulloblastoma cell line, D283 Med, appears to be cytogenetically stable even after passage 121. Stem line number was determined to be 46, with intact X and Y chromosomes. The cell line is characterized by the presence of four marker chromosomes (M1 to M4).

Do pediatricians independently manage common neurologic problems?

Quality educational programs should ensure that pediatricians possess current knowledge, skills, values, and attitudes in child neurology. The aim of this study was to examine the relationship between pediatricians' self-confidence in neurology and their frequency of referral of children to neurologists. We distributed a questionnaire to pediatricians and pediatric trainees for self-assessment of their (1) knowledge and skill in performing a neurologic examination, (2) ability to interpret neurologic findings, (3) knowledge of factual information about diseases of the nervous system, (4) ability to determine the need for investigations, and (5) ability to develop a positive attitude toward neurologic diseases. While pediatricians had significantly (P < .01) higher self-assessment scores than pediatric trainees, 54.2% of pediatricians referred 90% or more of their patients with neurologic complaints to neurologists; 74.9% of pediatricians referred more than 50% of such children to neurologists. Interestingly, pediatricians who referred over 90% of their patients to neurologists showed a significantly lower self-assessment score (P = .006) than did other pediatricians in knowledge and skill in performing a neurologic examination. As neurologists, we should develop educational programs that encourage pediatric trainees to learn to provide comprehensive care to children with common neurologic complaints.

Possible role of high-dose corticosteroids in the treatment of cat-scratch disease encephalopathy.

Approximately 2% of the estimated 24,000 patients in the United States who contract cat-scratch disease annually develop neurologic complications. Between 1989 and 1999, 36 patients were admitted to our hospital with cat-scratch disease; 25% had neurologic complications, and the majority experienced lengthy hospital stays. We describe a case of cat-scratch disease encephalopathy in a 4-year-old girl who responded to high-dose corticosteroid therapy. Further studies are warranted to determine if corticosteroid therapy shortens the duration of symptoms, lessens the severity of disease, and ultimately improves the outcome for patients with cat-scratch disease encephalopathy.

Neurobehavioral development in Joubert syndrome.

Research on children with Joubert syndrome has focused on brain structural abnormalities and associated clinical symptoms. The degree of developmental delay has not been objectively reported. We investigated the neurobehavioral development of children with Joubert syndrome through neurobehavioral assessment in the largest sample to date. Thirty-two parents of children with Joubert syndrome completed the Child Development Inventory and magnetic resonance imaging (MRI) data was gathered on 17 of these children. Results indicate that 94% were severely impaired according to the Child Development Inventory, with age being positively correlated with degree of neurobehavioral impairment. The average developmental age of our sample was 19 months (63% below chronological age). Severity of illness as measured by the General Development scale of the Child Development Inventory and severity of illness as measured by MRI (overall severity rating) did not yield consistent data regarding severity of the midbrain and cerebellar malformations. Similarly, markers of abnormal cerebral development such as cortical atrophy and delayed myelination were independent of severity of illness ratings on the Child Development Inventory. The degree of developmental delay in Joubert syndrome and the severity of gross central nervous system malformations appear independent.

Magnetic resonance imaging features and classification of central nervous system malformations in Joubert syndrome.

This article examines the magnetic resonance imaging features that typify the Joubert malformation. Specific morphologic features include: (1) dysgenesis of the isthmic portion of the brain stem at the pontomesencephalic junction, (2) abnormally thick superior cerebellar peduncles perpendicular to the brain stem, (3) hypoplasia of the cerebellar vermis with consequent enlargement of the 4th ventricle and rostral shift of the fastigium, and (4) sagittal vermic clefting. At least two of these features were present in every patient and all were present in some. The only cerebral anomaly identified was mild prominence of the ventricles and subarachnoid spaces. The "Joubert-plus anomaly" has been defined as the Joubert malformation plus additional anomalies of either the mesencephalon or the caudal 4th ventricle; this likely represents a similar but more extensive embryologic defect. By placing a relative numeric value on each morphologic feature, a classification scheme has been created that can quantitate the extent of the Joubert malformation in any individual case.

Brainstem and other malignant gliomas: II. Possible mechanisms of brain infiltration by tumor cells.

Gliomas that arise in the brain stem and other malignant gliomas constitute approximately 60% of all brain tumors and have eluded effective therapy, in part because they are able to infiltrate the normal brain. Histopathologic studies have confirmed the presence of infiltrating tumor cells very distant from the glioma mass. We review the neuroimaging and pathologic features of glioma-cell infiltration and some of the complex cellular and biochemical determinants of tumor-cell motility and invasiveness. Understanding how glioma cells become motile and invasive is pivotal to therapeutically targeting the machinery that enables gliomas to infiltrate the brain.

Clinical features and revised diagnostic criteria in Joubert syndrome.

The clinical presentation of children with Joubert syndrome can include nonspecific features such as hypotonia, ataxia, and developmental delay. Careful examination of the face shows a characteristic appearance, and a neuro-ophthalmologic examination shows the presence of oculomotor apraxia. In the neonatal period, most children have hyperpnea intermixed with central apnea. Neuroimaging of the head in the axial plane demonstrates the "molar tooth sign"--deep posterior interpeduncular fossa, thick and elongated superior cerebellar peduncles, and hypoplastic or aplastic superior cerebellar vermis. The central nervous system malformation spectrum observed in radiologic and neuropathologic studies accounts for many clinical features of Joubert syndrome. The developmental delay and cognitive impairment cannot be fully explained by the hindbrain malformation and probably result from dysfunction of the cerebral hemispheres. Although related conditions with vermian hypoplasia or aplasia (including Arima; Senior-Loken; and cerebellar vermian hypoplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis syndromes) can mimic Joubert syndrome, detailed imaging data are lacking in such cases. We propose a revision in diagnostic criteria for Joubert syndrome.

Gene therapy for neurologic disease: benchtop discoveries to bedside applications. 2. The bedside.

Important advances in basic research have made it possible to examine the safety, toxicity, and efficacy of gene therapy in humans for over 5 years. The development of sophisticated gene delivery systems has resulted in approval by the Recombinant DNA Advisory Committee (RAC) of 125 gene therapy or gene marking studies. One of the primary applications of current retroviral-mediated gene insertion technology has been for malignant brain tumors. Studies are therefore underway to examine the efficacy of "suicide" gene therapy in children with recurrent brain tumors and adults with newly diagnosed or recurrent gliomas. Since a high proportion of genetic disorders produce neurologic dysfunction, gene therapy is likely to impact the management of neurologic disease in the foreseeable future. Patients with human immunodeficiency virus (HIV), Gaucher's disease, and Hunter syndrome are now enrolled in gene therapy trials. It will be challenging for the child neurologist to stay abreast of rapid developments in the field of gene therapy. By participating in the design and implementation of clinical trials in gene therapy, the neurologist may reduce the intense toll that several neurologic diseases take on children and their families.

Gene therapy for neurologic disease: benchtop discoveries to bedside applications. 1. The bench.

The overall goal of this review is to provide the pediatric neurologist with a theoretical foundation in gene therapy. Gene therapy became feasible in the early 1970s and the first transfer of a foreign gene into humans was approved by the NIH in 1989. Adenovirus, adeno-associated virus, herpes-simplex virus, retroviruses, and other vectors have been used to efficiently transduce genes into cells in vitro and in vivo. We discuss laboratory experiments that have provided a strong scientific rationale for implementing human clinical trials of gene therapy for neurologic malignancy. The development of viral and nonviral vectors that mediate efficient gene insertion into human cells has created the prospect of using gene therapy for cancer or brain disease. The NIH has approved more than 100 gene therapy protocols since 1989. However, the field will require more research on gene delivery systems before gene therapy becomes an established therapeutic strategy for an array of central nervous system diseases.