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On September 27, 2006, the U.S. Food and Drug Administration granted approval to panitumumab (Vectibixtrade mark, Amgen, Inc., Thousand Oaks, CA) for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Panitumumab approval is based on the results of a single, open-label, randomized, multinational study that enrolled 463 patients with EGFR-expressing (at least 1+ membrane staining in >/=1% of tumor cells) metastatic colorectal cancer. Patients were randomized to either best supportive care (BSC) alone or BSC plus panitumumab, 6 mg/kg i.v., every other week. The primary study endpoint was progression-free survival (PFS), determined by an independent review committee that was blinded as to treatment assignment. BSC patients who progressed were eligible to receive panitumumab. The study patients' median age was 62 years, with 40% aged >/=65; 63% were male, 99% were white, 86% had a baseline Eastern Cooperative Oncology Group performance status score of 0 or 1, and 67% had colon cancer. The median time from diagnosis of metastases was approximately 19 months and the median number of prior therapies was 2.4. The PFS duration was significantly longer among patients randomized to receive panitumumab in addition to BSC (n = 231) compared with BSC alone (n = 232). The median and mean PFS times were 56 and 96.4 days, respectively, for patients receiving panitumumab and 51 and 59.7 days, respectively, for patients receiving BSC alone. Nineteen partial responses (8%, 95% confidence interval [CI], 5.3%-12.5%) were observed in panitumumab treated patients. The median duration of response was 17 weeks (95% CI, 16-25 weeks). Approximately 75% of patients in the BSC alone arm crossed over to receive panitumumab after disease progression. There was no difference in overall survival between the two study arms. The most common adverse events were skin rash, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea. The most serious adverse events were pulmonary fibrosis, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, diarrhea, and constipation. Disclosure of potential conflicts of interest is found at the end of this article. [ABSTRACT FROM AUTHOR]

This study verified the resistance to displacement of six miniplate fixation methods after sagittal split osteotomy (SSO). SSO was performed in 30 polyurethane synthetic mandible replicas. The distal segments were advanced (4 mm) and specimens were grouped according to the fixation method: four-hole standard miniplate; four-hole locking miniplate; six-hole standard miniplate; six-hole locking miniplate; six-hole standard sagittal miniplate; six-hole locking sagittal miniplate. Biomechanical evaluation was performed by applying compression loads to three points on the second molar region, using an Instron universal testing machine until a 3mm displacement of the segments occurred. Compression loads able to produce 3mm displacement were recorded in kN and subjected to analysis of variance (P<0.01) and Tukey's tests for comparison between groups (P<0.05). The locking sagittal miniplate showed higher resistance to displacement than the regular four- and six-hole locking and standard miniplates. No significant differences were observed between the locking sagittal miniplate and the regular sagittal or the four-hole locking miniplates. Two of the three groups with the best results had locking plate fixation methods. Fixation of SSO with a single miniplate is better accomplished using six-hole locking sagittal miniplates, six-hole standard sagittal miniplates, or four-hole locking miniplates; these methods are more resistant to displacement., (Copyright © 2012 International Association of Oral and Maxillofacial Surgeons. All rights reserved.)

This in vitro study evaluated the influence of the type of miniplate and the number of screws installed in the proximal and distal segments on the stability and resistance of Champy's osteosynthesis in mandibular angle fractures. Sixty polyurethane hemimandibles with bone-like consistency were randomly assigned to four groups (n=15) and sectioned in the mandibular angle region to simulate fracture. The bone segments were fixed by different osteosynthesis methods using 2.0 mm miniplates and 2.0 mm × 6 mm monocortical screws. In groups 1 and 2, two conventional (G1) or locking (G2) screws were installed in each bone segment using a conventional (G1) or a locking (G2) straight miniplate; in groups 3 and 4, three conventional (G3) or locking (G4) screws were installed in the proximal segment and four conventional (G3) or locking (G4) screws were installed in the distal segment using a conventional (G3) or a locking (G4) seven-hole straight miniplate. The hemimandibles were loaded in compressive strength until a 4mm displacement occurred between the segments, vertically or horizontally. Locking plate/screw systems provided significantly greater resistance to displacement than conventional ones (p<.01). Locking miniplates offered more resistance than conventional miniplates. Long locking miniplates provided greater stability than short ones., (Copyright © 2010 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Purpose: The aim of this in vitro study was to assess the biomechanical stability of 9 different osteosynthesis methods after sagittal split ramus osteotomy by simulating the masticatory forces and using a 3-point biomechanical test method., Materials and Methods: Forty-five polyurethane hemimandibles with bone-like consistency were randomly assigned to 9 groups (n = 5) and subjected to sagittal split ramus osteotomy. After 4-mm advancement of the distal segment, the bone segments were fixed by different osteosynthesis methods using 2.0-mm miniplate/screw systems: group A, one 4-hole conventional straight miniplate; group B, one 4-hole locking straight miniplate; group C, one 4-hole conventional miniplate and one bicortical screw; group D, one 4-hole locking miniplate and 1 bicortical screw; group E, one 6-hole conventional straight miniplate; group F, one 6-hole locking straight miniplate; group G: two 4-hole conventional straight miniplates; group H, two 4-hole locking straight miniplates; and group I, 3 bicortical screws in an inverted-L pattern. All models were mounted on a base especially constructed for this purpose. Using a 3-point biomechanical test model, the hemimandibles were loaded in compressive strength in an Instron machine (Norwood, MA) until a 3-mm displacement occurred between segments vertically or horizontally. Data were analyzed by analysis of variance and Tukey test (alpha = 1%)., Results: The multiparametric comparison of the groups showed a statistically significant difference (P < .01) between groups that used 2 miniplates (groups G and H), 1 miniplate and 1 bicortical screw (groups C and D), and only bicortical screws (group I) compared with groups that used only 1 miniplate with 2 screws per segment (groups A and B) and 3 screws per segment (groups E and F)., Conclusion: The placement of 2.0-mm-diameter bicortical screws in the retromolar region, associated or not with conventional and locking miniplates with monocortical screws, promoted a better stabilization of bone segments. Locking miniplates presented a better performance in bone fixation in all groups., (2010 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

A 15-year-old Asian male was referred to the department of oral and maxillofacial surgery at Tufts University School of Dental Medicine (TUSDM) for evaluation of a radiolucent lesion on the posterior left mandible. The patient was initially evaluated by his primary dentist for pain of two months' duration associated with teeth #17 and 18. Radiographic examination was performed and the panoramic radiograph revealed a radiolucent lesion involving the left mandibular body and ascending ramus, along with resorption of the roots of the predetermined teeth. Considering odontogenic infection, the patient was placed on antibiotics and referred to TUSDM for further evaluation and treatment.

A sixty-five year old white male presented with an acquired Factor V inhibitor after an episode of cholecystitis and cefotaxime therapy. Plasma Factor V activity was less than 1%. He developed lower gastrointestinal bleeding a week after onset of coagulopathy, and was treated with plasmapheresis, fresh frozen plasma, oral cyclophosphamide, and prednisone. The coagulopathy resolved within four days of treatment, and within two weeks of presentation. Laboratory studies revealed an IgG inhibitor to Factor V that closely mimicked the more commonly encountered lupus anticoagulant. We would like to alert clinicians to this entity because, in contrast to a lupus anticoagulant, the acquired Factor V inhibitor can be associated with clinical bleeding as in our patient, and requires therapy prior to any surgical procedures.

Objectives: The first objective was to determine the effect of inherited differences in the classic pathway complement protein C4 on complement activation by heparin-protamine complexes in cardiac surgery. Specifically, we hypothesized that patients with heterozygous C4A null phenotype (A0BB), who have decreased amounts of C4A, may have increased complement activation because of reduced clearance of heparin-protamine complexes. The second objective was to determine whether heparin-protamine-induced complement activation correlated with postoperative pulmonary shunt fractions., Methods: C4 typing was performed by agarose gel immunofixation and crossed immunoelectrophoresis. Complement activation was measured by radioimmunoassay of C3a and C4a before cardiopulmonary bypass, after bypass, and after protamine infusion. Shunt fractions were calculated from blood gases., Results: Of the 79 patients, 18 expressed heterozygous C4A null allele (A0BB), 16 had heterozygous C4B null allele (AAB0), three had homozygous C4B null alleles (AA00), and the rest expressed both C4A and C4B alleles (AABB). Patients with heterozygous C4A null allele had significantly increased plasma levels of C4a after protamine neutralization of heparin (C4a of 2862 +/- 375 ng/ml; mean +/- standard error of the mean) when compared with patients with normal expression of C4 alleles (AABB) (C4a of 1580 +/- 141 ng/ml) or heterozygous C4B null allele (C4a 1526 +/- 208 ng/ml). Pulmonary shunt fractions obtained after the operation correlated with the classic pathway complement activation by heparin-protamine complexes, but not with alternative pathway complement activation during cardiopulmonary bypass., Conclusions: Patients with heterozygous C4A null phenotype have increased complement activation by heparin-protamine complexes during cardiac operations, possibly because of their defective clearance. The classic pathway complement activation by heparin-protamine interaction correlates with postoperative pulmonary shunt fractions.

The present study evaluated complement activation during decompression after air dives in a hyperbaric chamber. Intravascular bubbles were quantified by Doppler ultrasound scoring. Eighteen subjects completed 92 dives, of which 74 produced bubbles. Complement activation was assessed by plasma C3a des Arg and red-cell-bound C3d before and after each dive. These parameters of in vivo complement activation failed to show significant activation. In vitro complement activation susceptibility tests on pre-dive sera were performed to explore their association with in vivo complement activation and intravascular bubbles. Such tests failed to identify a distinct complement-sensitive group and did not correlate with in vivo complement activation during the dives and/or intravascular bubble appearance. Two subjects developed decompression sickness but were not different from the rest of the group regarding in vitro complement sensitivity or complement activation during dives.

ALT and anti-HBc came into use in the US as surrogate tests for non-A, non-B hepatitis by 1986-1987, generally using cutoffs at 50-60 IU/L. We studied the usefulness of anti-HBc, and of ALT at different cutoffs as surrogate tests for hepatitis C virus, recording and analyzing the ALT, anti-HBc, HBsAg, and RIBA results of 175 non-autologous blood donations in 1993 and 1994 that had positive second generation screening tests for anti-HCV. ALT levels of 1014 blood donations also were studied. Only 93 of 175 anti-HCV-positive donations were RIBA positive. Of these, anti-HBc would have excluded 23%, an ALT cutoff at 60 IU/L would have excluded 42% and an ALT cutoff at 40 IU/L would have excluded 70% (plus 5.6% of all donations). Both tests together would have been better than either alone. No tests for HBsAg were positive. ALT and anti-HBc clearly were useful surrogate tests for hepatitis C. If they had been used sooner and with lower ALT cutoffs, many people would have avoided post-transfusion hepatitis in the years before anti-HCV testing was available.

The relationship between neutrophil activation and complement activation during open heart surgery was evaluated by measuring plasma lactoferrin and C3a des Arg (C3a) in 30 adult patients undergoing coronary artery surgery. Measurements were made before induction of anesthesia, before cardiopulmonary bypass, at the end of bypass, and 10 min after protamine infusion. Changes in the measured parameters thus reflected activation during the three distinct phases of cardiac surgery: pre cardiopulmonary bypass, the bypass phase, and the heparin neutralization phase. A major rise in lactoferrin occurred in the pre bypass period, from 99 +/- 13 (mean +/- SEM) to 647 +/- 48 ng/ml (p < 0.001). During this time, C3a levels did not rise significantly (384 +/- 22 to 439 +/- 36 ng/ml). The bypass procedure resulted in a rise of both lactoferrin and C3a levels, with lactoferrin reaching 1,092 +/- 69 ng/ml and C3a increasing to 1,884 +/- 179 ng/ml after bypass (p < 0.001 for both). In individual patients, however, the changes in lactoferrin during bypass did not correlate with changes in C3a levels (r = -0.06). After protamine infusion, C3a levels reached 3,301 +/- 324 ng/ml, while the plasma lactoferrin levels declined to 522 +/- 57 ng/ml. Thus, during open heart surgery, neutrophil activation, as measured by plasma lactoferrin concentration, does not correlate with complement activation resulting from the bypass procedure or the protamine neutralization of heparin. The potential clinical relevance of the neutrophil granular release of lactoferrin is discussed.

There have been several new developments in the field of autoimmune neutropenia over the past decade. Neutropenia caused by antibodies directed against granulocyte precursor cells, the oligoclonal nature of antineutrophil antibodies, and the expanding knowledge of neutrophil antigens, particularly in relationship to autoantibodies, are exciting new areas of investigation. Knowledge has also been advanced in the effector mechanisms of neutrophil autoantibodies and the effect of autoantibodies on the neutrophil function. In addition, some clinical syndromes of immune neutropenia have been better defined over the past decade, such as autoimmune neutropenia of infancy and chronic idiopathic neutropenia in adults. The past decade also saw interesting developments in the treatment of immune neutropenia, particularly in the use of gammaglobulin preparations and more recently in the advent of hematopoietic growth factors. This review focuses on these newer aspects of autoimmune neutropenia.

Quantitation of complement activation by polyacrilonitrile (PAN) dialyzer membrane is complicated by the high adsorptive capacity of the membrane for fluid phase anaphylotoxins. Assays for these anaphylotoxins, therefore, underestimate the degree of complement activation produced by this membrane. Alternative methods of measuring in vitro complement activation by the PAN and Cuprophan membranes were explored by incubating normal human erythrocytes with the membranes in the presence of serum. This led to deposition of C3d on these "innocent bystander" red cells, and provided an independent parameter for measuring complement activation. The PAN membrane caused significantly more C3d deposition on red cells, and thus more complement activation than Cuprophan. The possible significance of complement activation by PAN membrane, in consideration of its property of binding the resultant anaphylotoxins, is discussed.

Serum granulocyte binding IgG, IgM, and the light chain composition of granulocyte binding immunoglobulins were measured in 58 adult subjects, including 8 normal individuals, 6 with Felty syndrome, 6 with chronic idiopathic neutropenia, 32 with B-cell chronic lymphocytic leukemia (CLL), and 6 with multiple myeloma. An abnormal kappa/lambda ratio of granulocyte binding immunoglobulins was detected in 12 of 32 patients with CLL. Neutropenia in patients with CLL did not correlate with an abnormal kappa/lambda ratio or excess granulocyte binding IgG, but did correlate with granulocyte binding IgM (P less than 0.02). Eight of the 12 patients (5 with chronic idiopathic neutropenia and 3 with Felty syndrome) with an immune neutropenia without underlying neoplastic disorder had light chain restricted granulocyte binding immunoglobulins. Of all patients' sera with light chain restriction, 76% were of lambda light chain isotype. Thus, the frequent detection of light chain restriction of granulocyte binding immunoglobulins is not a reflection of malignancy but is suggestive of the somatic mutation of immunoglobulin light chain genes.

Complement activation may be responsible for some of the symptoms of decompression sickness. In the present study, complement activation was studied by exposing human sera with or without red blood cells to nitrogen bubbles. Nitrogen bubbles activated human complement as measured by generation of the fluid-phase, complement-split product C5a des Arg. In addition, we found that complement activation continued after exposure to bubbles was stopped. This continued complement activation may explain the failure of recompression treatment in some patients. Complement activation induced by nitrogen bubbles in human sera was enhanced when red cells were present. Red cells may be able to provide a stable membrane surface on which complement activation by bubbles can occur more efficiently. Complement activation by nitrogen bubbles in serum also led to the binding of activated C3 to red cells. Quantitation of bystander red-cell-bound C3d may allow the assessment of complement activation occurring by nitrogen bubbles in individuals undergoing decompression.

Purpose: The present study was done to evaluate the clinical characteristics of a large series of adult patients with chronic idiopathic neutropenia, and correlate the presence of antineutrophil antibodies, their class (IgG or IgM), and their ability to fix complement with clinical parameters, including other hemocytopenias, splenomegaly, and infections., Patients and Methods: One hundred twenty-one adult patients with chronic idiopathic neutropenia were studied. Serum neutrophil-binding antibodies were measured using paraformaldehyde-fixed granulocytes (PFGs) from normal volunteers as target cells. 125I-labeled staphylococcal protein A was used to detect IgG antibodies while IgM antibodies were detected by using 125I-labeled mouse monoclonal anti-IgM antibody. Sera containing antineutrophil antibodies were tested for their ability to fix complement on donor PFGs by using 125I-labeled monoclonal antibody to the third component of complement., Results: Of the 121 patients with chronic idiopathic neutropenia, 71 patients had isolated neutropenia, while 50 had neutropenia combined with either anemia and/or thrombocytopenia. Among the 71 patients with isolated neutropenia, there were 51 females (72%), compared with 28 females (56%) among the 50 patients with combined hemocytopenias (p = 0.083). Patients with multiple hemocytopenias were significantly older (p less than 0.01), were more likely to demonstrate splenomegaly (p = 0.001), and may have had more infectious complications. From all the patients, 36% of sera were shown to have antineutrophil antibodies, with a non-significant trend for these to be found more frequently in patients with multiple hemocytopenias. Sera with mixed IgG-IgM antineutrophil antibodies were significantly more likely to fix complement than those with isolated IgG or IgM antibodies, and among the patients with antineutrophil antibodies, complement-fixing antibodies were significantly associated with multiple hemocytopenias. Splenomegaly was significantly associated both with antineutrophil antibodies (p = 0.008) and with infections (p = 0.007). Antineutrophil antibodies were not associated with infections., Conclusions: Approximately one third of adult patients with idiopathic neutropenia have IgG and/or IgM antineutrophil antibodies demonstrable in their serum. There is a subset of patients with idiopathic neutropenia with multiple hemocytopenias who tend to be older, less likely to show female predominance, more likely to have splenomegaly and infections, and more likely to have antineutrophil antibodies, especially mixed IgG-IgM and complement-fixing antibodies.

A 73-year-old woman developed an acquired factor VIII inhibitor in association with squamous cell carcinoma of the epiglottis. The inhibitor was an IgG antibody that reacted with factor VIII in vitro and in vivo. Intravenous gamma-globulin therapy was successful in reducing the inhibitor so that curative surgery could be undertaken. With surgical resection of the tumor the inhibitor did not recur. The relevance of this type of coagulation disorder to the surgical management of the patient's head and neck cancer is discussed.