Intrathecal Chemotherapy Injection Research Articles

Fentanyl inhibits acute myeloid leukemia differentiated cells and committed progenitors via opioid receptor-independent suppression of Ras and STAT5 pathways.

Fentanyl is a common sedative/analgesic used for intrathecal chemotherapy injection in children with acute leukemia. Given the contradictory findings that fentanyl has both inhibitory and stimulatory activities in cancer cells, we investigated the biological effects of fentanyl alone and its combination with standard of care in acute myeloid leukemia (AML) cells at all stages of development. We showed that fentanyl at clinically relevant concentration inhibited growth and colony formation of AML differentiated cells and committed progenitors without affecting their survival. Compared to AML cells without FLT3 mutation, cells harboring FLT3-ITD mutation are likely to be more sensitive to fentanyl. However, fentanyl did not affect the most primitive AML stem cells. Fentanyl significantly augmented the efficacy of cytarabine but not midostaurin in AML differentiated cells and committed progenitors. We further demonstrated that fentanyl inhibited AML cells via suppressing Ras/Raf/MEK/ERK and STAT5 pathway, and this was not dependent on opioid receptor system. Our findings demonstrate the anti-leukemia activity of fentanyl and synergistic effects between fentanyl and cytarabine in AML, via opioid receptor-independent suppression of Ras and STAT5 pathways. Our work is the first to suggest the beneficial effects of fentanyl in children with leukemia.

HIGH INFECTION RELATED MORTALITY IN PAKISTANI CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKAEMIA DURING REMISSION INDUCTION CHEMOTHERAPY: REVIEW OF DATA FROM A SINGLE INSTITUTION

Purpose: Despite advances in the treatment of acute lymphoblastic leukaemia (A.L.L.), the outcome for children living in the developing countries is still poor. This is in large part due to high treatment-related mortality (TRM). This study was carried out to review the data and analyze the factors resulting in high TRM during remission induction chemotherapy. Methods: Data for children treated at our centre during the calendar year 2007 were retrospectively analysed. Standard four-drug induction chemotherapy was used without risk strati cation. Bone marrow evaluation was carried out at days 8 and 28. Cerebrospinal uid analysis was carried out on day 1 and with each subsequent intrathecal chemotherapy injection. Modern supportive care facilities including antibiotics, nutritional support and intensive care unit were available. Results: Eighty-one children were eligible for analysis. Median age was 5 years (range 2–16), 72% were male with M:F ratio of 2.5:1. Seventy- five (92%) children had precursor B-cell A.L.L. Only 2 children had central nervous system leukaemia at presentation. Median presenting white blood cell count was 8.83 (range: 1–446). Severe malnutrition (weight <5th centile for age) was seen in 42% of children. Median symptom duration was 6 (range 1–30) weeks at the time of presentation. Induction mortality was 25%. Induction mortality was 25.6% (n = 21). Twenty were related to infections, while more than half (52%) occurred as a result of an outbreak of Acinetobacter infection. Severe malnutrition and Acinetobacter infection (due to an outbreak in our unit during the study period) were highly predictive of TRM during remission induction chemotherapy. Conclusions: Infection control measures, health education and reduction in treatment intensity may improve survival for children with A.L.L. in Pakistani population. Key words: Acute lymphoblastic leukaemia in children, malnutrition, Pakistan, treatment-related mortality

Novel method for the detection and quantification of malignant cells in the CSF of patients with leptomeningeal metastasis of lung cancer.

The aim of the present study was to discuss a novel method for the detection of malignant tumor cells in cerebrospinal fluid (CSF), by observing tumor marker-immunostaining fluorescence in situ hybridization (TM-iFISH) enrichment and by counting CSF malignant tumor cells in patients with lung cancer leptomeningeal metastasis (LM). A total of 10 CSF samples were collected from 6 patients that presented with lung cancer LM. For each patient, 20 ml CSF was obtained through a lumbar puncture, of which 7.5 ml was used to count the number of malignant tumor cells in the CSF using TM-iFISH enrichment. Cytological and biochemical examinations were conducted on the remaining 10 ml and 2.5 ml CSF, respectively. The 10 CSF samples were successfully analyzed by TM-iFISH, and the tumor cell count range was 3–1,823 cells/7.5 ml CSF in 7 of the samples detected. There were no tumor cells detected in the remaining 3 samples. Tumor cells were revealed in 3 of the samples through the CSF cytological examinations, and albumin protein levels were indicated to be greater than the normal range (normal range, 0.15–0.45 g/l), in 9 of the samples using CSF biochemical examinations. Additionally, TM-iFISH was performed again to count the CSF malignant tumor cells in 3 of the patients following intrathecal injection of chemotherapy (methotrexate 10 mg and dexamethasone 5 mg). The results indicated that the malignant tumor cell count of 2 of the patients had decreased in comparison to the pre-treatment cell count. As it is capable of enriching and counting CSF malignant tumor cells in patients with lung cancer LM, TM-iFISH may be an effective method to diagnose lung cancer LM and to evaluate its efficacy.

Rapid sedation induced by fentanyl combined with propofol via an intrathecal chemotherapy injection for leukemia in children.

This study explored the sedative and analgesic effects of fentanyl combined with propofol via an intrathecal chemotherapy injection for acute leukemia (acute lymphocytic leukemia or acute myelocytic leukemia) among children, to relieve pain and difficulty during intrathecal injection, improve treatment compliance, increase the success rate of single puncture, and reduce procedure failure, with the aim of developing a painless procedure for children with acute leukemia. Fifty person-times received fentanyl combined with propofol via an intrathecal chemotherapy injection among the hospitalized children with leukemia. The patients' cooperation with the procedure, response to the medication, dosages of fentanyl and propofol, reaction to the procedures, wake-up time, and changes in oxygen saturation (SpO2), heart rate (HR), respiration, and blood pressure (BP) before, during, and after the procedures were observed. The doctors who performed the procedures assessed the quality of sedation and analgesia. In the treatment group, the patients were quiet during the lumbar puncture and intrathecal injection, showing good sedation and analgesia. HR and respiration decreased slightly. There were no changes in SpO2 and BP. No obvious respiratory depression occurred with proper dosages. Only a few patients showed stertorous respiration, which stopped soon after the procedures. In the control group, the patients were agitated, crying, and not cooperative before and during the procedures, which made the procedures very difficult. During intrathecal injection, pain obviously reduced and the success rate of single lumbar puncture increased. It is safe and effective to apply fentanyl combined with propofol for sedation and analgesia.

Recent Advancements of Treatment for Leptomeningeal Carcinomatosis.

Treatment of Leptomeningeal carcinomatosis (LMC) from solid cancers has not advanced noticeably since the introduction of intra-cerebrospinal fluid (CSF) chemotherapy in the 1970's. The marginal survival benefit and difficulty of intrathecal chemotherapy injection has hindered its wide spread use. Even after the introduction of intraventricular chemotherapy with Ommaya reservoir, frequent development of CSF flow disturbance, manifested as increased intracranial pressure (ICP), made injected drug to be distributed unevenly and thus, the therapy became ineffective. Systemic chemotherapy for LMC has been limited as effective CSF concentration can hardly be achieved except high dose methotrexate (MTX) intravenous administration. However, the introduction of small molecular weight target inhibitors for primary cancer treatment has changed the old concept of 'blood-brain barrier' as the ultimate barrier to systemically administered drugs. Conventional oral administration achieves an effective concentration at the nanomolar level. Furthermore, many studies report that a combined treatment of target inhibitor and intra-CSF chemotherapy significantly prolongs patient survival. Ventriculolumbar perfusion (VLP) chemotherapy has sought to increase drug delivery to the subarachnoid CSF space even in patients with disturbed CSF flow. Recently authors performed phase 1 and 2 clinical trial of VLP chemotherapy with MTX, and 3/4th of patients with increased ICP got controlled ICP and the survival was prolonged. Further trials are required with newly available drugs for CSF chemotherapy. Additionally, new LMC biologic/pharmacodynamic markers for early diagnosis and monitoring of the treatment response are to be identified with the help of advanced molecular biology techniques.

Diagnosis of central nervous system relapse of pediatric acute lymphoblastic leukemia: Impact of routine cytological CSF analysis at the time of intrathecal chemotherapy.

Despite the success of central nervous system (CNS) directed therapy in pediatric acute lymphoblastic leukemia (ALL), relapse involving the CNS continues to be observed in 5-10% of children when utilizing standard intrathecal prophylactic chemotherapy. While most pediatric ALL treatment protocols mandate regular lumbar punctures (LP) for the intrathecal injection of chemotherapy, the value of routine cytological analysis of cerebrospinal fluid (CSF) during therapy is unknown. Our objective was to assess the diagnostic value of routine CSF analysis during ALL therapy. To allow for at least 10 years of follow up from ALL diagnosis, children (0-18 years) with ALL diagnosed and treated at SickKids, Toronto, Canada between 1994-2004 were studied. Medical records of patients with CNS relapse were examined to determine whether CNS relapse was diagnosed based on cytology of a routinely obtained CSF sample, a CSF sample obtained because of signs and symptoms or a CSF sample obtained after the diagnosis of a bone marrow relapse. Of 494 children treated for ALL, 31 (6.6%) developed a relapse of ALL involving the CNS. Twenty-two had an isolated CNS relapse and nine had a combined bone marrow and CNS relapse. Among patients with isolated CNS relapse, 73% (16/22) were diagnosed based on routine CSF samples obtained from asymptomatic children. Conversely, 89% (8/9) of children with combined bone marrow and CNS relapse presented with symptoms and signs that prompted CSF examination. Routine CSF examination at the time of LP for intrathecal chemotherapy is useful in detecting CNS relapse.

Results of AIEOP LNH‐97 protocol for the treatment of anaplastic large cell lymphoma of childhood

Anaplastic large cell lymphoma (ALCL) represents approximately 15% of all pediatric non-Hodgkin lymphomas (NHL). It has distinct clinical features, including frequent involvement of extranodal sites and rare localization to the central nervous system (CNS). Despite varying treatment approaches the outcome of patients with ALCL has not significantly improved during the last two decades. From October 1997 to beginning of 2000, newly diagnosed ALCL patients were enrolled into AIEOP LNH-97 protocol for ALCL. Thereafter and until 2007, only CNS positive patients were included. AIEOP LNH-97 was based on the BFM-95 schema for ALCL and included six high-dose chemotherapy courses. CNS prophylaxis was obtained with one intrathecal injection of chemotherapy in each course, whereas treatment of CNS involvement included three intrathecal injections without irradiation. Thirty-two patients were eligible for the study. Lymph-node disease was the most frequent localization (69% of the cases), followed by mediastinal (25%), CNS (22%), bone marrow (16%), and skin (13%) involvement. Probabilities of overall survival (OS) and of event-free survival (EFS) at 5 years for the whole population were 87% (SE 6%) and 68% (SE 8%), respectively. This study confirmed that short pulse chemotherapy is an efficacious treatment option for first line therapy of pediatric ALCL, and that dose intensity may have some relevance for outcome, but not in all of the patients. Refinement and optimization of therapy strategies for ALCL may originate from a combination of clinical and biological prospective studies, as those in the pipeline of current international collaboration.

Postdural Puncture Headache: Incidence and Risk Factors in Children Following Intrathecal Chemotherapy

How to Cite this Article: Bani hashem A, Heydarian F, Gharavi M, Khoshnod M. Postdural Puncture Headache: Incidence and Risk Factors in Children FollowingIntrathecal Chemotherapy. Iranian Journal of Child Neurology 2012;6(1):19-22. Objective To evaluate the incidence and risk factors of development of postdural puncture headache in children who had intrathecal chemotherapy injection. Materials & Methods Two-hundred eighty patients (mean age, 7.23±3.92 years) who had intrathecal chemotherapy injection were studied prospectively during 2008-2009 in the pediatric ward of Dr. Sheikh hospital in Mashhad. Patients who had lumbar puncture for their chemotherapy drug injections were assessed daily for four days to detect postdural puncture headache. Results There were 172 (61, 4%) male patients and the remainder were female. Postdural puncture headache was detected in 41 patients (14.6%). The body mass index did not show any significant difference between the two groups. Lumbar puncture (LP) attempts had a significant association with postdural puncture headache. The size and shape of the needle did not have a significant association with postdural puncture headache. Conclusion LP attempts have a significant relationship with postdural puncture headache.

Volume of Cerebrospinal Fluid Removal Prior to Intrathecal Chemotherapy Administration: A Survey of Canadian Hematology/Oncology Practitioners,

Abstract 4196 Introduction:Intrathecal (IT) chemotherapy is administered to patients with leukemia to treat both central nervous system (CNS) disease and to prevent the spread of leukemia into the CNS. No studies that assess the exact volume of cerebrospinal fluid (CSF) that needs to be removed prior to the administration of IT chemotherapy exist, even though guidelines are published in some pediatric chemotherapy treatment protocols. We plan to study the side effects of different volumes of CSF removal prior to IT chemotherapy administration on patient quality of life in a randomized controlled trial. Prior to that study, we collected data on the practices of IT chemotherapy administration by hematology/oncology practitioners at the 17 pediatric oncology centers in Canada. Methods:We designed a 12 question survey, which was sent electronically to all hematology/oncology practitioners in Canada who perform lumbar puncture (LP) with IT chemotherapy administration. Included in our survey were consultants, nurse practitioners, pediatricians, clinical assistants and fellows. We identified practitioners using the Children's Oncology Group member database and verified our lists by contacting the head of each Canadian hematology/oncology division, as well as the training program director at each of these centers, to ensure all eligible practitioners were included. Three follow up email reminders about the survey were sent to the same group of practitioners. The data was collected electronically and descriptive statistics were obtained. Results:We identified a total of 178 pediatric hematology/oncology practitioners at all Canadian centers who perform LPs with IT chemotherapy. The survey was completed by 112 (62.9%) of these individuals of whom 107 performed LPs with IT chemotherapy and 5 did not. Of these respondents, 65.4% were consultant pediatric hematologist/oncologists, 24.3% were fellows in pediatric hematology/oncology, 6.5% were clinical assistants, 2.8% were nurse practitioners, and 0.9% were pediatricians. Thirty one percent had been practicing hematology/oncology for more than 15 years, 27.1% for less than 5 years, 26.2% for 5–10 years, and 15.9% for 10–15 years. Most respondents (29.9%) reported that 6–10 LPs with IT chemotherapy are performed at their institution every week, followed by 11–15 (17.8%), 0–5 (13.1%) and 21–25 (11.2%). Most respondents had performed more than 500 LPs with IT chemotherapy (45.3%) in their career to date, followed by 34% having performed 100–500 LPs with IT chemotherapy.The volume of CSF removal prior to IT chemotherapy administration varied among respondents. The most common volume removal was 3 ml (17.9%), followed by half the volume of IT chemotherapy administered (15.1%), then 2 and 4 ml (14.2% each), then 1 ml (13.2%) and finally equal to the total volume of IT chemotherapy injected (9.4%). Chemotherapy was injected over 30–60 seconds 41.9% of the time, followed by over less than 30 seconds (28.6%) and over 1–2 minutes (19%). The majority of practitioners learned how much CSF to remove and the speed with which to inject IT chemotherapy from a consultant hematologist/oncologist (88.8%). A little more than a half were aware that protocols have guidelines on how much CSF to remove (58.1%), and of those aware of these guidelines the majority (57.1%) do not follow them. When asked practitioners to list all of the reasons for why they did not follow the recommended guidelines, and the reasons given were that they were not obligatory (41.9%), that there was no evidence for the guidelines (40.0%), that there was pressure from those around to perform the procedure and administer the IT chemotherapy quickly (32.3%), and that practitioners themselves did not have the time to collect all of the CSF recommended (29.0%). Conclusions:This large survey of Canadian pediatric hematology/oncology practitioners, assessing the practice of IT chemotherapy administration, showed that there is large variation in the volume of CSF that is removed prior to IT chemotherapy administration and the speed of IT chemotherapy injection. In the majority of cases, published guidelines in chemotherapy treatment protocols are not followed. A study examining the side effects of different volumes of CSF removal will provide much needed evidence for this clinical procedure. Disclosures:No relevant conflicts of interest to declare.

Resolution of extensive leptomeningeal metastasis and clinical spinal cord compression from breast cancer using weekly docetaxel chemotherapy

Metastatic breast cancer to the leptomeninges is a late event in the disease course and is associated with significant morbidity and a grave prognosis. Treatment typically involves direct intrathecal injection of chemotherapy into the cerebrospinal fluid compartment since systemic chemotherapy penetrates poorly to the central nervous system. Here we report an interesting clinical observation involving a patient presenting with leptomeningeal spread of breast cancer causing extensive spinal cord compression with obliteration of the subarachnoid space, thus precluding the use of direct intrathecal chemotherapy. We administered systemic chemotherapy using weekly docetaxel with complete radiographic resolution of her disease and recovery from clinical spinal cord compression. While this is a single clinical observation, weekly administration of docetaxel in this circumstance may have been associated with improved drug "escape" into the central nervous system and better antitumor effect. Because leptomeningeal disease is typically a late event in metastatic breast cancer, resistance to therapeutic intervention may reflect intrinsically resistant disease in the setting of extensive prior therapy rather than a routine problem with systemic drug delivery to the CNS. Studying patterns of disease relapse in patients who had received adjuvant weekly taxanes may provide insights into this hypothesis.

Outcome of Umbilical Cord Blood Transplantation in 51 Patients with Hematologic Malignancies.

Abstract 4342 Background and ObjectivesUmbilical cord blood transplantation (UCBT) has recently emerged as a curative approach for patients with hematologic malignancies who lack a suitable HLA-matched donor. We report the outcome of UCBT for 51 hematologic malignancies from a single hospital in Southeast China. Design and MethodsFifty-one cases of UCBT for hematologic malignancies at Anhui Provincial Hospital from March 2000 to May 2009 were retrospectively characterized, including 20 cases of acute lymphoblastic leukemia (ALL), 12 acute myeloid leukemia (AML), 12 chronic myeloid leukemia (CML) (accelerated phase 5, blast crisis 4), 2 mixed acute leukemia(MIX-AL),4 myelodysplastic syndrome (MDS), and one case of non-Hodgkin lymphoma (NHL). Double UCB grafts were used for 27 patients, while single UCB graft was used for 24 patients. All but one UCB grafts were from unrelated donors. The median cell doses infused were 4.37×107TNC/kg (range, 2.41?16.24), 2.96×105 CD34/kg (range, 0.67?29.28) in single UCBT or 4.44×107TNC/kg (range, 2.76?7.70), 2.67×105 CD34/kg (range, 0.8?9.35) in double UCBT. Myeloablative conditioning was given to 46 patients and nonmyeloablative regimen was given to 5 patients according to the standard protocols. Myeloablative regimen consisted of fractionated total body irradiation (TBI) 1,200 cGy, cyclophosphamide 120 mg/kg, cytarabine 8g/m2 (n=26) or of modified BUCY2 consisting of busulfan 16mg/kg orally or 12.8 mg/kg intravenously, cyclophosphamide 120 mg/kg, and rabbit antithymocyte globulin (ATG, Fresenius, Germany) 7.5mg/kg (n=20). Reduced intensity conditioning consisted of fludarabine 160 mg/m2, BU6.4m/kg, ATG 7.5mg/kg and TBI 3Gy. All patients were given a combination of cyclosporin A (CsA) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. ResultsOf the 51 patients, 34 had advanced stage of disease. The patients' age ranged from 3 to 48 years (median 19 yr) and the body weight ranged from 15 to 84 kg (median 53 kg), respectively. Although one patient with advance-staged chronic myeloid leukemia (CML) died 16 days after UCBT and 6 patients showed primary graft failure, 44 of the 50 patients (88%) achieved engraftment, with neutrophil recovery (≥0.5×109/L) occurring at a median of 19 days (range, 12-39) and platelet recovery (≥20×109/L) occurring at a median of 34 days (range, 21-73), respectively. All of the 44 patients gained complete donor chimerism by PCR analysis of short tandem repeat (STR) sequences on whole blood or bone marrow from day 7 to day 100 after transplantation. Half of the patients (22/44, 50%) developed acute GVHD with 19 cases of grade I/II disease (43.2%) and 3 cases of grade III disease (6.8%). Only five patients (16.1%) developed chronic GVHD, with 2 in skin, 1 in intestinal, 1 in liver, and 1 patient with refractory chronic GVHD with thrombocytopenia. Three patients had relapse (2 year relapse rate of 5.9%) with one in central nervous system, who achieved remission after intrathecal injection of chemotherapy regimen.,one with CML blast crisis achieved remission after oral imatinib,and the third died of relapsed disease. The median follow-up duration of surviving patients was 19 months (range, 3-113) with a 2 year overall survival rate of 54.5%. A total of 20 patients died during the study, with a 2 year transplant related mortality rate of 37.3%. The most common cause of death was severe infection (12) due to bacteria, fungi and/or viruses, and other causes included acute GVHD (1), disease progression (1), veno-occlusive disease of the liver (1), sudden cardiac death (1), cerebral hemorrhage (1), fulminant viral hepatitis (1), early rejection (1),and systemic failure (1). Interpretation and ConclusionsUCBT could be safely and effectively used for patients with hematologic malignancies. The use of double UCB as a strategy extends the availability of transplantation. Prevention and control of infection are essential for long-term survival after UCBT. Disclosures:No relevant conflicts of interest to declare.

Methotrexate—exploring dosing and administration in ALCL

Central nervous system prophylaxis is recommended with the administration of high-dose methotrexate and/or intrathecal injection of chemotherapy in patients with anaplastic large-cell lymphoma (ALCL). Researchers investigated whether methotrexate dose, infusion duration and intrathecal mode of administration had an impact on the risk of systemic and central nervous system relapses in children with ALCL.

Delay of the diagnostic lumbar puncture and intrathecal chemotherapy in children with acute lymphoblastic leukemia who undergo routine corticosteroid testing: Tokyo Children's Cancer Study Group study L89-12.

To determine the effects of eliminating initial lumbar punctures in 418 consecutively treated children with acute lymphoblastic leukemia (ALL). Patients were enrolled onto a trial conducted in central Japan between 1989 and 1992. Treatment consisted of standard four-drug induction therapy followed by a risk-based intensification phase, reinduction therapy, late intensification, and remission maintenance therapy (total of 104 weeks). The initial lumbar puncture, with an intrathecal injection of chemotherapy, was performed after 1 week of prednisolone sensitivity testing (day 8). End points included response to prednisolone, CNS status at the time of the day 8 lumbar puncture, subsequent adverse events in CNS and bone marrow, and event-free survival (EFS). The remission induction rate was 93.1% with a 6-year EFS rate (+/- SE) of 68.7% +/- 2.4%, which is similar to historical results for patients who received their diagnostic lumbar puncture and first instillation of intrathecal chemotherapy on day 0. Overall, 84.5% of the patients had good responses to prednisolone, whereas 15.5% had poor responses. Clinical outcome was strikingly better for the good responders (6-year EFS, 74.1% +/- 2.5% compared with 40.1% +/- 6.4% for patients with poor responses), suggesting that omission of intrathecal chemotherapy did not alter the predictive value of drug sensitivity testing. Eighteen patients experienced CNS relapse as their first adverse event (cumulative risk, 5.1%; 95% confidence interval, 2.7% to 7.4%), coincident with reports from groups using conventional strategies of CNS clinical management. Bleeding into the CSF at the time of the day 8 lumbar puncture was apparent in 29 cases (8.1%), but leukemic blasts were identified in only two. Delay of the initial lumbar puncture and intrathecal injection of chemotherapy seems to be feasible in children with ALL. Further controlled evaluations are needed to establish the validity of this conclusion.