Cellular interactions between axon terminals containing endogenous opioid peptides or corticotropin-releasing factor in the rat locus coeruleus and surrounding dorsal pontine tegmentum

Recent evidence suggests that certain stressors release both endogenous opioids and corticotropin-releasing factor (CRF) to modulate activity of the locus coeruleus (LC)-norepinephrine (NE) system. In ultrastructural studies, axon terminals containing methionine(5)-enkephalin (ENK) or CRF have been shown to target LC dendrites. These findings suggested the hypothesis that both neuropeptides may coexist in common axon terminals that are positioned to have an impact on the LC. This possibility was examined by using immunofluorescence and immunoelectron microscopic analysis of the rat LC and neighboring dorsal pontine tegmentum. Ultrastructural analysis indicated that CRF- and ENK-containing axon terminals were abundant in similar portions of the neuropil and that approximately 16% of the axon terminals containing ENK were also immunoreactive for CRF. Dually labeled terminals were more frequently encountered in the "core" of the LC vs. its extranuclear dendritic zone, which included the medial parabrachial nucleus (mPB). Triple labeling for ENK, CRF, and tyrosine hydroxylase (TH) showed convergence of opioid and CRF axon terminals with noradrenergic dendrites as well as evidence for inputs to TH-labeled dendrites from dually labeled opioid/CRF axon terminals. One potential source of ENK and CRF in the dorsal pons is the central nucleus of the amygdala (CNA). To determine the relative contribution of ENK and CRF terminals from the CNA, the CNA was electrolytically lesioned. Light-level densitometry revealed robust decreases in CRF immunoreactivity in the LC and mPB on the side ipsilateral to the lesion but little or no change in ENK immunoreactivity, confirming previous studies of the mPB. Degenerating terminals from the CNA in lesioned rats were found to be in direct contact with TH-labeled dendrites. Together, these data indicate that ENK and CRF may be colocalized to a subset of individual axon terminals in the LC "core." The finding that the CNA provides, to dendrites in the area examined, a robust CRF innervation, but little or no opioid innervation, suggests that ENK and CRF axon terminals impacting LC neurons originate from distinct sources and that terminals that colocalize ENK and CRF are not from the CNA.     

A phase II study of concomitant hyperfractionated radiation therapy and double dose intra-arterial cisplatin for squamous cell carcinoma of the head and neck

This successor phase II study evaluates the tolerability and efficacy of concomitant hyperfractionated radiation therapy (HFX-RT) and double dose intra-arterial (IA) cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In doing so, this study represents further resurgence of the potential use of IA chemotherapy in the management of SCCHN. This has been enabled by the evolution of angiographic catheter/microcatherter technology. Between 1997 and 1999, 24 patients with locally advanced T4/T3 SCCHN were treated with HFX-RT (76.8- 81.6 Gy at 1.2 Gy bid over 6-7 weeks) and high-dose IA cisplatin (150mg/m2 given at the start of and during RT boost treatment [start of week 6 and 7]). Twenty-two patients (92%) had T4 disease and 14 (58%) N2/ N3 disease. Acute toxicity was limited to two grade 4 (8%) and 19 grade 3 (79%) mucosal events; and single grade 3 hematologic, infectious and skin events. Eight patients (33%) were unable to receive the second planned dose of IA cisplatin. Twenty-two patients had complete response (92%) at the primary site. Among 17 patients with positive neck disease 12 (71%) achieved complete response in the neck. Follow-up ranges from 7-30 months (median = 18 months) with 14 patients alive without disease, 2 alive with disease, 7 dead of disease and 1 dead of intercurrent disease. While concomitant HFX-RT and double dose IA cisplatin as used in this study is associated with encouraging response rates in this highly unfavorable subset of patients with locally advanced SCCHN it was not feasible. Future investigation of this novel treatment strategy utilizing modern angiographic catheter/microcatherter technology will involve a single dose of IA cisplatin with HFX-RT and dose intensification using neoadjuvant therapy.     

Interval pathologic assessments in patients treated with concurrent hyperfractionated radiation and intraarterial cisplatin (HYPERRADPLAT)

BACKGROUND: To minimize surgical morbidity, surgery should be performed within 2 to 3 months of completion of radiation therapy with or without chemotherapy. Pathologic demonstration of cancer at this interval is commonly used to justify early surgical salvage of residual primary head and neck cancer. These assumptions regarding head and neck cancer in patients treated with concurrent hyperfractionated radiation therapy and intraarterial supradose cisplatin (HYPERRADPLAT) have never been evaluated. METHODS: Post-HYPERRADPLAT clinical and pathologic findings in 42 patients with stage III and IV head and neck cancer were compared with their disease outcomes. All patients underwent an interval analysis of response at 6 to 10 weeks after completion of therapy, 28 of these patients had biopsies of the primary tumor site performed. RESULTS: Clinical findings of cancer with pathologic confirmation up to 4 months after therapy can be associated with eventual complete response (CR). Pathologic CR's from deep incisional biopsies can be associated with recurrent disease within 2 months. Six HYPERRADPLAT-treated patients underwent interval surgical resection of primary disease, and only the four patients with cancer identified in the resection specimen died of recurrent disease. CONCLUSION: In patients treated with HYPERRADPLAT, interval clinical and pathologic assessments may be misleading. Only observation of progressive disease is an accurate predictor of local failure. New evaluation techniques such as metabolic imaging and molecular analysis warrant exploration as tools for interval cancer evaluations.     

The role of dose size in a chemotherapy regimen (ProMECE-CytaBOM) for the first-line treatment of large B-cell lymphomas: a randomized trial by the Gruppo Italiano Studio Linfomi (GISL).

BACKGROUND: It is still unclear the actual contribute of dose intensity (DI), dose size (DS) and dose density (DD) in the conventional chemotherapy of large, B-cell non-Hodgkin lymphomas. METHODS: A prospective, randomized trial compared the cyclic schedule of ProMECE-CytaBOM chemotherapy (cyc-PC, 6 cycles) with a modified version of it, which administered the same drugs sequentially (seq-PC), with the same planned cumulative DI and an 83% DD, within the same time frame (113 days), but with three times higher DS of all the drugs except vincristine. RESULTS: Fifty-six patients received cyc-PC and 52 seq-PC. The actual mean cumulative DI was 0.79 +/- 0.15 with cyc-PC, 0.78 +/- 0.17 with seq-PC. Response was complete in 59% and 52%, partial in 20% and 21%, null in 5% and 6%, respectively. There were four toxic deaths (two per arm). Relapses occurred in 36% and 37%, respectively. Toxicity was similar in both arms. Overall, failure-free, progression-free and disease-free survival (median follow-up: 54 months) were statistically indifferent. CONCLUSIONS: The very similar DI actually delivered in both arm seems to be the main common determinant of the indifferent results recorded. Increasing DS--at least within the limits clinically attainable without stem cell rescue--does not improve results.     

Calf pseudohypertrophy in a patient with double neurogenic pathology

A pseudohypertrophy of the calf can be rarely associated with neurogenic pathologies as S-1 radiculopathy, poliomyelitis, spinal muscular atrophy, traumatic lesions of peripheral nerves, intraspinal neurinoma. The causes of this particular phenomenon are unknown. The authors present the case of a 52-year-old man with an enlargement of the left calf suffering from a mild form of spinal paralytic poliomyelitis in the early childhood and episodes of severe left sciatica in the last four years. Electromyography demonstrated a pattern of denervation in both legs and an H-reflex absent when the left tibial nerve was stimulated. An open muscle biopsy of the left calf was performed. Light microscopic and ultrastructural examination of the muscle confirmed the presence of a pattern of "neurogenic type" pseudohypertrophy. Our results could be interesting for the understanding of the mechanism of neurogenic pseudohypertrophy. This case suggests that timing of stimulus or "dose" of denervation may be important factors in such a phenomenon.     

Peripheral blood stem cell transplantation: Impact on procedure load and workload in an apheresis unit

Peripheral blood stem cells (PBSC) reinfusion appears to hasten hematologic reconstitution following myeloablative therapy. While procurement of PBSC adds apheresis procedures, rapid engraftment could decrease the demand for platelet transfusions. To determine the impact of PBSC collection on workload in our apheresis unit, we studied 3 consecutive groups of patients with metastatic breast cancer given comparable high-dose chemotherapy and autologous bone marrow transplant, with or without PBSC or granulocyte-colony stimulating factor (G-CSF). Forty-one transplants were performed with bone marrow cells only: 31 patients (Group A) did not receive G-CSF, while the following 10 patients (group B) received daily G-CSF until neutrophil engraftment. Bone marrow cells and PBSC were used for the most recent 11 transplants (group C), followed by daily G-CSF until engraftment. PBSC were mobilized with cyclophosphamide (4 g/m²) and etoposide (1 g/m²), followed by G-CSF, 8 μg/kg/day. PBSC collection was carried out on a Fenwal CS3000 + cell collector, using modified procedure 1, to obtain a minimum of 5 × 10⁸ mononuclear cells/kg. The times to neutrophil count over 500/μL, platelet count over 20,000/μL, and discharge from the hospital after transplant were significantly shorter for patients in group C (medians of 8, 8, and 21 days, respectively) compared to group A (medians of 14, 14, and 29 days; P = 0.001) or group B (medians of 11, 24, and 32 days; P < 0.001). The number of single-donor platelet equivalents transfused (1 SDE = 1 unit of single-donor platelets or 8 pooled random-donor platelets) was significantly decreased in group C (median = 4) compared to group A (median = 19) and group B (median = 11; P = 0.001 for both comparisons). The total apheresis procedure load (the sum of SDE and PBSC collection for each transplant) was significantly decreased in group C (median = 6) compared to groups A and B combined (median = 14; P = 0.001). The apheresis unit workload assessing apheresis durations per patient, calculated as 2 × SDE + 4 × PBSC, was also significantly reduced in group C (median = 16) compared to groups A and B (median = 28; P = 0.002). Thus, PBSC were advantageous in terms of faster engraftment, reduced platelet transfusions, and shorter hospitalization, while decreasing both procedure load and net workload per patient in the apheresis unit. © 1992 Wiley-Liss, Inc.     

Sulfoalkyl ether-alkyl ether cyclodextrin derivatives, their synthesis, NMR characterization, and binding of 6alpha-methylprednisolone

The objective of this study is to see if random alkyl ethers of various sulfoalkyl ether cyclodextrins can be synthesized and characterized. The purpose of the alkylation was to test the hypothesis that an increase in the "height" of a cyclodextrins cavity would help in the binding/complexation of larger more structurally complex molecules. The synthesis of new cyclodextrin derivatives comprising a mixture of sulfoalkyl ether and alkyl ether substituents on the same cyclodextrin ring was performed in aqueous alkaline solutions using various sultones and alkylsulfates. The method presented provided an easy and efficient way to modify cyclodextrins avoiding the use of organic solvents and high quantities of alkylating agents and could be carried out in either a two step or "one pot" single step process. Purification was by neutralization followed by ultrafiltration. The derivatives were characterized by 1D, ((1)H and (13)C), and a 2D NMR technique (HMQC, Heteronuclear Multiple Quantum Coherence). The combination of these techniques allowed an analysis of the degree of substitution and the site of substitution on the cyclodextrin (CD) nucleus. For both beta- and gamma-CD, sulfoakylation was preferred on the 2 > 3 > 6 hydroxyls while alkylation was preferred 6 > 2 > 3. Due to the simultaneous presence of short alkyl ether chains and negatively charged sulfoalkyl ether chains, these mixed water-soluble cyclodextrin derivatives, especially those of gamma-cyclodextrin, should be able to bind more complex drugs. The improved binding capacity of these new modified CDs with the model drug 6alpha-methylprednisolone is reported.     

The acetabular reamer: a unique tool for anterior iliac crest bone graft harvesting

Bone grafting is often required in craniofacial reconstruction. Morselized corticocancellous bone grafts are particularly useful in applications such as filling and contouring irregular bony defects. Obtaining grafts of this consistency by traditional methods is difficult. An efficient harvesting method that can produce such grafting material in clinically useful quantities is needed. We report the use of a mechanical acetabular reamer for the purpose of harvesting a bone graft from the iliac crest.     

Superior vena cava thrombus treated with low-dose, peripherally administered recombinant tissue plasminogen activator in a child: case report and review of the literature

Thrombotic complications in pediatrics are more common today due to our ability to treat complicated diseases. In pediatric patients where thrombolytic therapy is indicated, the lack of evidence-based medicine forces practitioners to extrapolate dose recommendations for recombinant tissue plasminogen activator (rt-PA) from adult studies. This often results in a high rate of major complications. Low-dose rt-PA is an option that is effective and safe. The authors describe a child with septic thrombus of the superior vena cava who was successfully treated with low-dose, peripherally administered rt-PA, and review the efficacy and safety of standard- versus low-dose rt-PA in children. A Medline search was completed for the use of standard- and low-dose rt-PA in children with thromboembolic disease. Five studies large enough to present efficacy and safety data on standard- and/or low-dose t-PA use in children and neonates were analyzed. Two studies using low-dose rt-PA reported efficacy rates equal to or greater than those reported for standard-dose regimens. Rates of major complications were approximately 5% for low-dose regimens and up to 40% for standard-dose ones. Low-dose, peripherally administered rt-PA is safe and may be as effective as standard-dose rt-PA. A randomized controlled trial should be done to confirm this assumption.