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.).

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.

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.

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.

Tuberous sclerosis.

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder characterized by widespread hamartomas in several organs, including the brain, heart, skin, eyes, kidney, lung, and liver. The affected genes are TSC1 and TSC2, encoding hamartin and tuberin respectively. The hamartin-tuberin complex inhibits the mammalian-target-of-Rapamycin (mTOR) pathway, which controls cell growth and proliferation. Variations in the distribution, number, size, and location of lesions cause the clinical syndrome to vary even between relatives. About 85% of children and adolescents with TSC have CNS complications, including epilepsy, cognitive impairment, challenging behavioral problems, and autism-like symptoms. Epilepsy generally begins during the first year of life, with focal seizures and spasms. The discovery of the mTOR pathway upregulation in TSC-associated lesions presents new possibilities for treatment strategy. Increasing understanding of the molecular abnormalities caused by TSC may enable improved management of the disease.

Joubert syndrome is not a cause of classical autism.

A previous report noted a 27% prevalence of autism in Joubert syndrome (JS), raising the question of overlapping etiologies. Family studies have shown that autism is characterized by family loading for a number of specific behavioral and psychiatric disorders and that the sib recurrence risk is around 4%. The purpose of this study is to determine whether children with Joubert and their families show behavioral or genetic characteristics similar to autism. Thirty-one volunteer Joubert families were identified. Parents completed a semi-structured family history interview and the Autism Behavioral Checklist. Rates of family loading for neuropsychiatric disorders in the JS families were compared to autism family history data and Down syndrome (DS) controls. The JS families had significantly lower rates of autism, alcoholism, cognitive, and language disorders than the autism families. Their rate of depression was lower, but not significantly different from that found in autism families. None of the JS children met the clinical cut-off for autism based on parental symptom report and the sib recurrence risk was 32% for the JS families compared to 4% for the autism and 0% for DS families. These data indicate that JS is a genetically distinct disorder from autism. Different genes with different inheritance patterns that affect neurodevelopment of the cerebellum could explain the clinical similarities previously reported in JS and autism.

Quantitative assessment of brainstem development in Joubert syndrome and Dandy-Walker syndrome.

Key features of Joubert syndrome include developmental delay, hypotonia, hyperpnea and apnea, oculomotor apraxia, and the presence of the molar tooth sign on axial imaging through the brainstem isthmus--the junction of the pons and mesencephalon. Interestingly, 1 in 10 patients with Joubert syndrome has abnormal cerebrospinal fluid collections misdiagnosed as Dandy-Walker variants. Because of important differences in patient management, genetic counseling, and prognosis between these conditions, we undertook a study to determine if the brainstem isthmus is normal in Dandy-Walker syndrome. Using standard landmarks, we evaluated development of the isthmus in normal subjects and in subjects with Joubert syndrome and Dandy-Walker syndrome. Four of five brainstem measures increased with age in normal subjects. In subjects with Joubert syndrome, the depth and length of the interpeduncular fossa were increased, and the width of the isthmus was decreased. In subjects with Dandy-Walker syndrome, the width of the brainstem isthmus was normal, and the molar tooth sign was absent. Although the pons can be hypoplastic in Dandy-Walker syndrome, we conclude that the pontomesencephalic junction is normal. Thus, the molar tooth sign can effectively distinguish between Joubert and Dandy-Walker syndromes. Genetic heterogeneity or epigenetic factors may account for abnormal cerebrospinal fluid collections in some cases of Joubert syndrome.

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.

Chromosome 17 loss-of-heterozygosity studies in benign and malignant tumors in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant condition characterized by benign tumor (neurofibroma) growth and increased risk of malignancy. Dermal neurofibromas, arising from superficial nerves, are primarily of cosmetic significance, whereas plexiform neurofibromas, typically larger and associated with deeply placed nerves, extend into contiguous tissues and may cause serious functional impairment. Malignant peripheral nerve sheath tumors (MPNSTs) seem to arise from plexiform neurofibromas. The NF1 gene, on chromosome segment 17q11.2, encodes a protein that has tumor suppressor function. Loss of heterozygosity (LOH) for NF1 has been reported in some neurofibromas and NF1 malignancies, but plexiform tumors have been poorly represented. Also, the studies did not always employ the same markers, preventing simple comparison of the frequency and extent of LOH among different tumor types. Our chromosome 17 LOH analysis in a cohort of three tumor types was positive for NF1 allele loss in 2/15 (13%) dermal neurofibromas, 4/10 (40%) plexiform neurofibromas, and 3/5 (60%) MPNSTs. Although the region of loss varied, the p arm (including TP53) was lost only in malignant tumors. The losses in the plexiform tumors all included sequences distal to NF1. No subtle TP53 mutations were found in any tumors. This study also reports the identification of both NF1 "hits" in plexiform tumors, further supporting the tumor suppressor role of the NF1 gene in this tumor type.

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.

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.

Parental burden, coping, and family functioning in primary caregivers of children with Joubert syndrome.

Children with Joubert syndrome have physical and intellectual disabilities. The purpose of this study was to assess the impact of Joubert syndrome on parental burden, coping, and family functioning. Forty-nine primary caregivers were surveyed. Forty-three primary caregivers were mothers and six were fathers; their mean age was 34 years. The following measures were used: Beck Depression Inventory, Child Development Inventory, Caregiver Strain Index, Family Assessment Device, and Ways of Coping Checklist-Revised. The data show that caregiver burden is not related to the severity of the child's illness, but that caregivers report significant burden. Higher burden was associated with the use of palliative coping methods, and family functioning was problematic. The results of this study suggest that for parents of children with Joubert syndrome, degree of parental burden depends more on the parents' coping skills and the level of family functioning rather than on the degree of the child's impairment. These findings highlight the importance of assessing caregiver burden, as well as decreased family functioning or coping abilities, since these problems often can be managed with psychologic intervention.

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.

Cognition, behavior, and development in Joubert syndrome.

This article reports on a series of studies of children with Joubert syndrome who were examined in three investigations from 1994 through 1998. Neuropsychologic screening of 10 of 40 children showed a variety of deficits in cognition, verbal memory, visuomotor, motor, and language-related tasks. Parent report of developmental attainments revealed only 3 of 40 children functioning in the borderline range, with the rest scoring in the severely impaired range. Parent reports of behaviors revealed problems in temperament, hyperactivity, aggressiveness, and dependency, as well as problems in physical development and care that were felt to be related to their neurologic handicaps. Future directions of research with this rare disorder are suggested.