Phase II study of cilengitide in the treatment of refractory or relapsed high-grade gliomas in children: A report from the Children's Oncology Group

Background

Cilengitide, an αv integrin antagonist, has demonstrated activity in recurrent adult glioblastoma (GBM). The Children''s Oncology Group ACNS0621 study thus evaluated whether cilengitide is active as a single agent in the treatment of children with refractory high-grade glioma (HGG). Secondary objectives were to investigate the pharmacokinetics and pharmacogenomics of cilengitide in this population.

Methods

Cilengitide (1800 mg/m²/dose intravenous) was administered twice weekly until evidence of disease progression or unacceptable toxicity. Thirty patients (age range, 1.1–20.3 years) were enrolled, of whom 24 were evaluable for the primary response end point.

Results

Toxicity was infrequent and mild, with the exception of one episode of grade 2 pain possibly related to cilengitide. Two intratumoral hemorrhages were reported, but only one (grade 2) was deemed to be possibly related to cilengitide and was in the context of disease progression. One patient with GBM received cilengitide for 20 months and remains alive with continuous stable disease. There were no other responders, with median time to tumor progression of 28 days (range, 11–114 days). Twenty-one of the 24 evaluable patients died, with a median time from enrollment to death of 172 days (range, 28–325 days). The 3 patients alive at the time of this report had a follow-up time of 37, 223, and 1068 days, respectively.

Conclusions

We conclude that cilengitide is not effective as a single agent for refractory pediatric HGG. However, further study evaluating combination therapy with cilengitide is warranted before a role for cilengitide in the treatment of pediatric HGG can be excluded.     

A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies: a pediatric brain tumor consortium study

High expression of ERBB2 has been reported in medulloblastoma and ependymoma; EGFR is amplified and over-expressed in brainstem glioma suggesting these proteins as potential therapeutic targets. We conducted a molecular biology (MB) and phase II study to estimate inhibition of tumor ERBB signaling and sustained responses by lapatinib in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, ependymoma, and high-grade glioma (HGG) undergoing resection were stratified and randomized to pre-resection treatment with lapatinib 900 mg/m² dose bid for 7–14 days or no treatment. Western blot analysis of ERBB expression and pathway activity in fresh tumor obtained at surgery estimated ERBB receptor signaling inhibition in vivo. Drug concentration was simultaneously assessed in tumor and plasma. In the phase II study, patients, stratified by histology, received lapatinib continuously, to assess sustained response. Eight patients, on the MB trial (four medulloblastomas, four ependymomas), received a median of two courses (range 1–6+). No intratumoral target inhibition by lapatinib was noted in any patient. Tumor-to-plasma ratios of lapatinib were 10–20 %. In the 34 patients (14 MB, 10 HGG, 10 ependymoma) in the phase II study, lapatinib was well-tolerated at 900 mg/m² dose bid. The median number of courses in the phase II trial was two (range 1–12). Seven patients (three medulloblastoma, four ependymoma) remained on therapy for at least four courses range (4–26). Lapatinib was well-tolerated in children with recurrent or CNS malignancies, but did not inhibit target in tumor and had little single agent activity.     

Clinico-radiologic characteristics of long-term survivors of diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG) is the deadliest central nervous system tumor in children. The survival of affected children has remained poor despite treatment with radiation therapy (RT) with or without chemotherapy. We reviewed the medical records of all surviving patients with DIPG treated at our institution between October 1, 1992 and May 31, 2011. Blinded central radiologic review of the magnetic resonance imaging at diagnosis of all surviving patients and 15 controls with DIPG was performed. All surviving patients underwent neurocognitive assessment during follow-up. Five (2.6 %) of 191 patients treated during the study period were surviving at a median of 9.3 years from their diagnosis (range 5.3–13.2 years). Two patients were younger than 3 years, one lacked signs of pontine cranial nerve involvement, and three had longer duration of symptoms at diagnosis. One patient had a radiologically atypical tumor and one had a tumor originating in the medulla. All five patients received RT. Chemotherapy was variable among these patients. Neurocognitive assessments were obtained after a median interval of 7.1 years. Three of four patients who underwent a detailed evaluation showed cognitive function in the borderline or mental retardation range. Two patients experienced disease progression at 8.8 and 13 years after diagnosis. A minority of children with DIPG experienced long-term survival with currently available therapies. These patients remained at high risk for tumor progression even after long follow-ups. Four of our long-term survivors had clinical and radiologic characteristics at diagnosis associated with improved outcome.     

Newer Innovations in Treatment of Retracted Nipple

Objectives

To compare the efficacy, merits and demerits of various methods for the treatment of retracted nipple, i.e., two new innovative methods (rubber band method and sucking by the husband) with the in-use syringe method.

Methods

A prospective study on 213 women having retracted nipple, 71 in each of the three groups was carried out. Group A included patients in which syringe method was used; Group B comprised of woman in which rubber band method was used and Group C included patients with vigorous sucking by the husband.

Results

Highest success rates were seen in Group C (vigorous sucking by the husband), being 52, 88 and 94 % on days 3, 7 and 14 respectively. Success rates in Group B (rubber band method) were lower, being 43, 66 and 74 % respectively and lowest in Group A (syringe method), i.e., 33, 47 and 64 %, respectively on corresponding days. Problem of difficulty in applying technique were common in Group B (38 %), less common in Group A (22 %) and nil in Group C. The incidence of local pain had the same trend i.e., 48 and 30 % in Group B and A, respectively, and nil in Group C. Disliking taste of milk in mouth and problem of privacy were highest in Group C i.e., 28 % and 100 % respectively.

Conclusions

Although syringe method is well established, sucking by husband is definitely superior and a boon for difficult cases too. Rubber band method is a bit inferior due to complicated technique, local pain and no lactation stimulation.     

Unresponsive ventricular tachycardia associated with aluminum phosphide poisoning

Inhalation or ingestion of aluminum phosphide (AP) generates phosphine gas on exposure to moisture, which, in turn, produces widespread organ toxicity primarily involving the lungs, heart, liver, and kidneys. Cardiac manifestations of AP poisoning include toxic myocarditis, refractory heart failure, bradyarrhythmias, and tachyarrhythmias including ventricular tachycardia (VT). A 19-year-old depressed male farm worker ingested ten 500-mg tablets of Celphos in a suicide attempt. Each Celphos tablet contains 56% AP. Over the course of 10 hours, the patient developed heart failure and respiratory failure associated with a rise in serum troponin level to 12.7 ng/mL. Serum electrolytes (including magnesium) and serum creatinine levels were normal throughout. His course was further complicated by acidemia and hypotension. These hemodynamic and metabolic abnormalities were initially corrected by assisted ventilation and continuous veno-venous hemofiltration. However, he developed hemodynamically stable sustained monomorphic VT, which proved unresponsive to treatment with intravenous magnesium sulfate and intravenous amiodarone therapy. After a decline in blood pressure, 6 attempts at electrocardioversion failed to restore sinus rhythm, and he died. Postmortem histologic examination of myocardium showed contraction band necrosis, early coagulation necrosis, edema, hemorrhage, and pyknosis of cardiac myocyte nuclei. Ventricular tachycardia associated with AP poisoning has been successfully treated with magnesium sulfate, amiodarone, and electrocardioversion. This case report documents failure of all 3 of these therapeutic modalities.     

Beyond "cirrhosis": a proposal from the International Liver Pathology Study Group

"Cirrhosis" is a morphologic term that has been used for almost 200 years to denote the end stage of a variety of chronic liver diseases. The term implies a condition with adverse prognosis due to the well-known complications of portal hypertension, hepatocellular carcinoma, and liver failure. However, recent advances in the diagnosis and treatment of chronic liver diseases have changed the natural history of cirrhosis significantly. This consensus document by the International Liver Pathology Study Group challenges the usefulness of the word cirrhosis in modern medicine and suggests that this is an appropriate time to consider discontinuing the use of this term. The role of pathologists should evolve to the diagnosis of advanced stage of chronic liver disease, with emphasis on etiology, grade of activity, features suggestive of progression or regression, presence of other diseases, and risk factors for malignancy, within the perspective of an integrated clinicopathologic assessment.     

DRB1*1502-DQB1*0601-DQA1*0103 and DRB1*04-DQB1*0302 in Jewish hypersomnolent patients

OBJECTIVES: Narcolepsy is a sleep disorder with a genetic association with the haplotype DRB1*1501, DQA1*0102, DQB1*0602. This haplotype has been described in different ethnic groups suffering from narcolepsy (Japanese, Caucasian, African Americans, Jews). In a recent study we have found the haplotype DRB1*1502, DQB1*0601, DQA1*0103 in three patients with hypersomnolence. The similarity of this haplotype to the narcoleptic haplotype DRB1*1501, DQB1*0602 and DQA1*0102 has raised the question of whether this haplotype is a marker for sleepiness, or rather indicates a variant of non-cataplectic narcolepsy. This study was conducted to further investigate this question. METHODS: HLA-DNA analysis was carried out in 20 healthy Jewish patients (age 23.9+/-6.3 years; 13 Ashkenazi, seven non-Ashkenazi) who had objective measures of hypersomnolence. All underwent whole-night polysomnography, multiple sleep latency test and tissue typing. RESULTS: HLA-DNA analysis revealed HLA-DR2 in eight patients of whom five (25%) carried the haplotype DRB1*1502, DQB1*0601, DQA1*0103 (vs. 1.4% in the Israeli population, P<0.0001). Six patients were diagnosed as non-cataplectic narcoleptics. Five of them carried the haplotype DRB1*1502, DQB1*0601, DQA1*0103. Forty percent of the patients carried the haplotype DRB1*04, DQB1*0302, which was not statistically different from its prevalence in the healthy Israeli population (25%). CONCLUSIONS: This is the first report describing the haplotype DRB1*1502, DQB1*0601, DQA1*0103 in narcoleptic patients (non-cataplectic). This haplotype is close but different from the already known narcoleptic haplotype DRB1*1501, DQA1*0102, DQB1*0602. We assume that this haplotype represents a variant of non-cataplectic narcolepsy rather than association with hypersomnolence. However, in order to conclude whether this haplotype is a marker for the lack of cataplexy, or represents a variant of non-cataplectic narcolepsy, a larger group of patients should be investigated.     

Inflammatory status in chronic renal failure: The role of homocysteinemia and pro-inflammatory cytokines

AIM: To evaluate determinants of inflammatory markers in chronic renal failure patients according to the level of glomerular filtration rate.METHODS: One hundred fifty four patients (Age: 44 ± 06 years; male/female: 66/88) with chronic renal failure (CRF) were divided into 6 groups according to the National Kidney Foundation (NKF) classification. They included 28 primary stage renal failure patients (CRF 1), 28 moderate stage renal failure patients (CRF 2), 28 severe stage renal failure patients (CRF 3), 18 end-stage renal failure patients (CRF 4), 40 hemodialysis (HD) patients, and 12 peritoneal dialysis (PD) patients. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and C-reactive protein (CRP) were analyzed by immunosorbent assay kit (ELISA) (Cayman Chemical’s ACETM EIA kit). Immunoassay methods were used for total homocysteine (tHcy) (fluorescence polarization immunoanalysis HPLC, PerkinEmer 200 series), transferrin (MININEPHTM human transferin kit: ZK070.R), ferritin (ADVIA Centaur) and fibrinogen analysis (ACL 200). Differences between groups were performed using SPSS 20.0 and data are expressed as the mean ± SD.RESULTS: Results showed that in comparison with CRF 1 group and other groups, TNF-α and IL-6 levels were respectively more elevated in HD (16.38 ± 5.52 pg/mL vs 0.39 ± 0.03 pg/mL, 11.05 ± 3.59 pg/mL vs 8.20 ± 0.22 pg/mL, P < 0.001) and PD (14.04 ± 3.40 pg/mL vs 0.39 ± 0.03 pg/mL, 10.15 ± 1.66 pg/mL vs 8.20 ± 0.22 pg/mL, P < 0.001). IL-1β levels were increased in HD (9.63 ± 3.50 pg/mL vs 3.24 ± 0.10 pg/mL, P < 0.001) and CRF 4 (7.76 ± 0.66 pg/mL vs 3.24 ± 0.10 pg/mL, P < 0.001) patients than in CRF 1 and in the other groups. Plasma tHcy levels were higher in HD (32.27 ± 12.08 μmol/L) and PD (28.37 ± 4.98 μmol/L) patients compared to the other groups of CRF (P < 0.001). The serum CRP level was significantly increased in HD (18.17 ± 6.38 mg/L) and PD (17.97 ± 4.85 mg/L) patients compared to the other groups of CRF patients (P < 0.001). The plasma fibrinogen level was more elevated in HD (6.86 ± 1.06 g/L) and CRF 4 (6.05 ± 0.57 g/L) than in the other groups (P < 0.001). Furthermore; the ferritin level was higher in HD (169.90 ± 62.16 ng/mL) and PD (90.08 ± 22.09 ng/mL) patients compared to the other groups of CRF (P < 0.001). The serum transferrin value was significantly decreased especially in PD (1.78 ± 0.21 g/L) compared to the other groups (P < 0.001). We found a negative correlation between glomerular filtration rate (GFR), TNF-α levels (r = -0.75, P < 0.001), and tHcy levels (r = -0.68, P < 0.001). We observed a positive correlation between GFR and transferrin levels (r = 0.60, P < 0.001).CONCLUSION: CRF was associated with elevated inflammatory markers. The inflammation was observed at the severe stage of CRF and increases with progression of renal failure.