Methotrexate-induced chemical meningitis in patients with acute lymphoblastic leukemia/lymphoma

Background:

Intrathecal methotrexate (ITMTX) is an important component in the treatment as well as prophylaxis of leukemia/lymphoma. ITMTX can cause chemical meningitis characterized by vomiting, headache, and fever lasting 2-5 days with spontaneous resolution of symptoms which differentiates this syndrome from bacterial meningitis.

Objective:

This prospective observational study was carried out to determine incidence of post-ITMTX syndrome in patients receiving prophylactic ITMTX as part of Berlin-Frankfurt-Munster (BFM) protocol.

Materials and Methods:

Patients aged 15-50 years receiving BFM 90 or BFM 95 protocol for acute lymphoblastic leukemia or lymphoblastic lymphoma were followed up for post-ITMTX syndrome, defined as vomiting, headache and fever between 38° and 39°C following ITMTX.

Results:

Thirty-three patients received a total of 297 courses of ITMTX. Of the 297 doses of ITMTX, 20 episodes (6.7%) of post-ITMTX syndrome were observed. The incidence of post-ITMTX syndrome was highest after the second dose of ITMTX (24%). The most common symptom of post-ITMTX syndrome was headache which was seen in 17 (85%) patients. Seventeen (85%) patients had vomiting, 10 (50%) patients had fever, and 4 (20%) patients had backache. Meningeal signs were present in 2 (10%) patients.

Conclusions:

Post-ITMTX syndrome is not uncommon in adult patients receiving prophylactic ITMTX for treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Patients develop a toxic syndrome closely mimicking acute bacterial meningitis but spontaneous recovery is seen without any neurological sequelae.     

Effect of concurrent radiochemotherapy and chemotherapy on serum proteins for prospective predictors of patients with HPV induced cervical cancer

Objectives

To evaluate the effectiveness of radiochemotherapy and chemotherapy on human papilloma virus induced cervical cancer patients by the estimation of serum proteins and magnetic resonance imaging.

Methods

HPV 16/18 viral DNA was detected in the plasma of cervical cancer patients (n = 50) by PCR using HPV consensus primers. Of the 50 cervical cancer patients, 25 cases undergoing radiation with chemotherapy and another 25 cases undergoing chemotherapy. Levels of pre- and post-treated serum squamous cell carcinoma antigen, soluble CD44, cancer antigen-125 were measured and evaluated the tumour size at pre- and post-radiation based on magnetic resonance images. The effectiveness of treatment was evaluated in terms of protein levels and represented as whisker line graphs.

Results

Of the amplified 50 samples, HPV 16 and 18 strains were identified as 48 and 44%, respectively. Serum protein levels were significantly increased in both pre-treated groups when compared to healthy group. Post-treated (radiotherapy) cervical cancer patients’ shows decreased tumour size when compared to pre-treated groups. Taking consideration of proteins, squamous cell carcinoma antigen, soluble CD44, cancer antigen-125 levels are more decreased in patients treated with radiochemotherapy than chemotherapy alone. The decreased levels of proteins were significantly higher in early stage of the cervical cancer than the advanced stage of cancer patients.

Conclusion

Serum levels of protein markers are more improved in patients treated with radiochemotherapy than chemotherapy hence, radiochemotherapy may be the best choice of treatment with reference to proteins at early stage of cervical cancer when compared to chemotherapy alone.     

Mn (III) tetrakis (4-benzoic acid) porphyrin administered into the intrathecal space reduces oxidative damage and neuron death after spinal cord injury: a comparison with methylprednisolone

The metalloporphyrin Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) is a cell-permeable superoxide dismutase mimetic and a broad-spectrum scavenger of reactive species. Since MnTBAP may not cross the blood-brain barrier, this study evaluated the therapeutic potential of MnTBAP to treat spinal cord injury (SCI; 25 g x cm) by directly administering it into the intrathecal space of the rat spinal cord. The cells in spinal sections removed at 24 h post-SCI were immunohistochemically stained with anti-4-hydroxynonenal (HNE), a marker of membrane lipid peroxidation (MLP); anti-nitrotyrosine (Ntyr), a marker of protein nitration; and anti-neuron-specific enolase (NSE) antibodies. Immunostained neurons were counted for quantitative evaluation. Pre-treatment 30 min before SCI with 1 mg/kg MnTBAP or 4-h post-SCI treatment with 2.5 mg/kg MnTBAP administered into the intrathecal space significantly reduced MLP and protein nitration, and increased the number of surviving neurons compared to vehicle controls. However, post-SCI treatment with a standard regimen of methylprednisolone sodium succinate (MPSS; 30 mg/kg followed by 5.4 mg/kg for maintenance, iv administration), the only drug used for clinical treatment of SCI, not only did not reduce MLP and neuron loss, it increased protein nitration compared with vehicle controls (two-way analysis of variance [ANOVA] followed by the Tukey test). These results demonstrate that pre- and post-intrathecal treatments with the low doses of MnTBAP provide sustained neuroprotection by preventing oxidative stress and that post-treatment with MnTBAP is superior to post-treatment with MPSS in preventing oxidative stress and resulting neuron loss.     

Synthesis of novel 3-[5-ethyl-2-(2-phenoxy-ethyl)-pyridin]-5-substituted isoxazoline libraries via 1,3-dipolar cycloaddition and evaluation of antimicrobial activities

A series of novel 3-[5-ethyl-2-(2-phenoxy-ethyl)-pyridin]-5-substituted isoxazolines were synthesized via 1,3-dipolar cycloaddition of in situ generated nitrile oxide from 4-[2-(5-ethylpyridyl)-ethoxy]-benzaldoxime with alkenes to obtain new heterocyclic libraries containing a pyridine moiety in addition to the isoxazoline ring. The newly synthesized compounds were screened for their antimicrobial activity and were compared with standard drugs. The compounds demonstrated potent to weak antimicrobial activity. Of the compounds studied, compounds 3c and 3f showed significant antibacterial as well as antifungal activity. Compounds 3e and 3g showed moderate activity. The title compounds represent a novel class of potent antimicrobial agents.     

Primary bone lymphoma: a report of two cases and review of the literature

Primary bone lymphoma (PBL) is an uncommon tumor accounting for approximately 4-5% of extra nodal lymphoma and less than 1% of all non-Hodgkin's lymphoma. Disease may be complicated at presentation by pathological fracture or spinal cord compression. Diffuse large-B-cell lymphoma (DLBCL) accounts for the majority of cases of PBL. Owing to its rarity, only a few retrospective studies have been published addressing the prognosis and treatment of primary bone lymphoma. In this paper, we report our experience with two cases of PBL treated with chemotherapy and radiotherapy and review literature to elucidate the optimal treatment of primary bone lymphoma.     

Bavituximab plus paclitaxel and carboplatin for the treatment of advanced non-small-cell lung cancer

Objective

Bavituximab is a phosphatidylserine (PS)-targeting monoclonal antibody with immune-modulating and tumor-specific vascular targeting properties. Preclinical studies have shown activity against numerous solid tumors and at least an additive effect in combination with chemotherapy. This study evaluated bavituximab in combination with paclitaxel and carboplatin in patients with previously untreated, locally advanced or metastatic non-small-cell lung cancer (NSCLC).

Patients and methods

This phase II, open-label study (NCT00687817) was conducted in 49 patients with stage IIIB/IV NSCLC utilizing a Simon two-stage design. Patients were treated with up to six cycles of carboplatin area under the concentration–time curve (AUC) 5 plus paclitaxel 175 mg/m² every 21 days with weekly bavituximab 3 mg/kg followed by bavituximab monotherapy until progression or unacceptable toxicity.

Results

The primary efficacy endpoint of overall response rate (ORR) was 40.8% (complete response [CR] 2.0%, partial response [PR] was 38.8%). Median progression-free survival (PFS) and overall survival (OS) were 6.0 and 12.4 months, respectively. Treatment-related adverse events (AEs) occurred in 40.8% of patients. The most common treatment-related AEs were anemia (10.2%), asthenia, vomiting, paresthesia, anorexia, and fatigue (6.1% each). One patient with a central, cavitating squamous tumor developed fatal hemoptysis and aspiration.

Conclusion

Bavituximab in combination with paclitaxel–carboplatin as first-line therapy demonstrated a tolerable safety profile and potential efficacy in this single-arm phase II trial in patients with advanced local or metastatic NSCLC. Randomized trials with this regimen are in progress.

ClinicalTrials.gov identifier

NCT00687817.     

A double-blind,randomised, placebo-controlled,phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer

BackgroundWe conducted a phase 2b, randomised, double-blind, placebo-controlled screening trial to evaluate the addition of the multikinase inhibitor sorafenib (antiproliferative/antiangiogenic) to first-line paclitaxel for human epidermal growth factor receptor 2 (HER2)-negative locally recurrent/metastatic breast cancer.MethodsPatients were randomised to paclitaxel (90 mg/m², weekly, intravenously, 3 weeks on/1 week off) plus sorafenib (400 mg, orally, twice daily) or placebo. The primary endpoint was progression-free survival (PFS). A sample size of 220 patients was planned with relative risk ?0.82 (1-sided α = 0.14) after 120 events supporting a treatment effect.FindingsPatients were randomised in India (n = 170), the United States (n = 52) and Brazil (n = 15). Median PFS was 6.9 months for sorafenib versus 5.6 months for placebo (hazard ratio (HR) = 0.788; 95% confidence interval (CI), 0.558–1.112; P = 0.1715 [1-sided P = 0.0857]). The addition of sorafenib increased time to progression (median, 8.1 versus 5.6 months; HR = 0.674; 95% CI 0.465–0.975; P = 0.0343) and improved overall response (67% versus 54%; P = 0.0468). Overall survival did not statistically differ (median, 16.8 versus 17.4 months; HR = 1.022; 95% CI 0.715–1.461; P = 0.904). Grade 3/4 toxicities (sorafenib versus placebo) included hand-foot skin reaction (31% versus 3%), neutropenia (13% versus 7%) and anaemia (11% versus 6%). Two treatment-related deaths occurred (malaria and liver dysfunction) in the sorafenib arm.InterpretationThe addition of sorafenib to paclitaxel improved disease control but did not significantly improve PFS to support a phase 3 trial of similar design. Toxicity of the combination was manageable with dose reductions.FundingNorthwestern University, Onyx Pharmaceuticals, Bayer Healthcare Pharmaceuticals.