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Biomedical subjects

Marshall R Posner

Publications and source records attributed to Marshall R Posner.

At least 19 recordsLinked to original sources
PubMed2006

Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin.

BACKGROUND: Pemphigus vulgaris is a potentially fatal autoimmune mucocutaneous blistering disease. Conventional therapy consists of high-dose corticosteroids, immunosuppressive agents, and intravenous immune globulin. METHODS: We studied patients with refractory pemphigus vulgaris involving 30% or more of their body-surface area, three or more mucosal sites, or both who had inadequate responses to conventional therapy and intravenous immune globulin. We treated the patients with two cycles of rituximab (375 mg per square meter of body-surface area) once weekly for 3 weeks and intravenous immune globulin (2 g per kilogram of body weight) in the fourth week. This induction therapy was followed by a monthly infusion of rituximab and intravenous immune globulin for 4 consecutive months. Titers of serum antibodies against keratinocytes and numbers of peripheral-blood B cells were monitored. RESULTS: Of 11 patients, 9 had rapid resolution of lesions and a clinical remission lasting 22 to 37 months (mean, 31.1). All immunosuppressive therapy, including prednisone, could be discontinued before ending rituximab treatment in all patients. Two patients were treated with rituximab only during recurrences and had sustained remissions. Titers of IgG4 antikeratinocyte antibodies correlated with disease activity. Peripheral-blood B cells became undetectable shortly after initiating rituximab therapy but subsequently returned to normal values. Side effects that have been associated with rituximab were not observed, nor were infections. CONCLUSIONS: The combination of rituximab and intravenous immune globulin is effective in patients with refractory pemphigus vulgaris.

Adolescent↗
PubMed2006

American Society of Clinical Oncology clinical practice guideline for the use of larynx-preservation strategies in the treatment of laryngeal cancer.

PURPOSE: To develop a clinical practice guideline for treatment of laryngeal cancer with the intent of preserving the larynx (either the organ itself or its function). This guideline is intended for use by oncologists in the care of patients outside of clinical trials. METHODS: A multidisciplinary Expert Panel determined the clinical management questions to be addressed and reviewed the literature available through November 2005, with emphasis given to randomized controlled trials of site-specific disease. Survival, rate of larynx preservation, and toxicities were the principal outcomes assessed. The guideline underwent internal review and approval by the Panel, as well as external review by additional experts, members of the American Society of Clinical Oncology (ASCO) Health Services Committee, and the ASCO Board of Directors. RESULTS: Evidence supports the use of larynx-preservation approaches for appropriately selected patients without a compromise in survival; however, no larynx-preservation approach offers a survival advantage compared with total laryngectomy and adjuvant therapy with rehabilitation as indicated. RECOMMENDATIONS: All patients with T1 or T2 laryngeal cancer, with rare exception, should be treated initially with intent to preserve the larynx. For most patients with T3 or T4 disease without tumor invasion through cartilage into soft tissues, a larynx-preservation approach is an appropriate, standard treatment option, and concurrent chemoradiotherapy therapy is the most widely applicable approach. To ensure an optimum outcome, special expertise and a multidisciplinary team are necessary, and the team should fully discuss with the patient the advantages and disadvantages of larynx-preservation options compared with treatments that include total laryngectomy.

Clinical Trials, Phase III as Topic↗
PubMed2006

Concurrent weekly docetaxel and concomitant boost radiation therapy in the treatment of locally advanced squamous cell cancer of the head and neck.

PURPOSE: In a Phase I/II trial, we investigated concurrent weekly docetaxel and concomitant boost radiation in patients with locally advanced squamous cell cancer of the head and neck (SCCHN) after induction chemotherapy. PATIENTS AND METHODS: Patients presented with American Joint Committee on Cancer Stage III/IV and were treated initially with induction chemotherapy using cisplatinum/5-fluorouracil (PF), carboplatinum-5-FU, or docetaxel-PF. Patients then received docetaxel four times weekly with concomitant boost (CB) radiation (1.8 Gy once-daily X20, 1.8/1.5 Gy twice a day). Fifteen patients each received 20 mg/M2 and 25 mg/M2. RESULTS: Thirty-one patients were enrolled and 30 were evaluable for response and toxicity. Median follow-up was 42 months (range, 27-63 months). Primary sites were: oropharynx 19, oral cavity 2, larynx/hypopharynx 5, and unknown primary 4. Eighty-seven percent of patients had N2/N3 disease; 60% had T3/T4 disease. Twenty percent of patients had a complete response (CR) to induction chemotherapy. After chemoradiotherapy, 21 of 30 patients had a CR, 2 had progressive disease, and 7 had partial response (PR). Nineteen of 26 patients presenting with neck disease had neck dissections, and 7 of 19 were positive. Ninety-three percent of all patients were rendered disease-free after all planned therapy. Treatment failed in 8 patients, and 7 have died of disease. An additional patient died with no evidence of disease. Twenty-one patients (70%) are currently alive with no evidence of disease. No acute dose-limiting toxicity was observed at either dose level. CONCLUSIONS: This intensive treatment regimen of concurrent docetaxel/concomitant boost radiation and surgery after induction chemotherapy in poor prognosis patients yields good local regional control and survival. Docetaxel/CB chemoradiotherapy represents an aggressive alternative regimen to platinum-based chemoradiotherapy or surgery in patients who have a poor response to induction chemotherapy.

Adult↗
PubMed2006

Pathogenic human monoclonal antibody against desmoglein 3.

Pemphigus vulgaris (PV) is a potentially fatal autoimmune mucocutaneous disease associated with production of IgG autoantibodies to desmoglein 3 (Dsg3), a 130-kDa epidermal cadherin protein. The binding of pathogenic antibody to Dsg3 on epidermal keratinocytes leads to loss of intercellular adhesion and results in intraepithelial blister formation. Here, we describe a human monoclonal antibody, PVMAB786, a Dsg3-specific IgG4 antibody, from an untreated patient with active PV. The antibody reacts with a 130-kDa protein on keratinocyte cell surfaces and recombinant Dsg3 protein, but not desmoglein 1 protein. PVMAB786 induces acantholysis in normal human skin and mucous membranes and induces a clinical and histological profile similar to human PV when injected into neonatal mice. PVMAB786 will be a valuable tool in identifying the role of Dsg3 in epithelial cell adherence and acantholysis, mechanisms of Dsg3 processing/presentation and V gene and isotype usage in PV pathogenesis.

Acantholysis↗
PubMed2006

Examining the need for neck dissection in the era of chemoradiation therapy for advanced head and neck cancer.

OBJECTIVES: To (1) determine clinical factors that predict pathologic complete response (pCR) on neck dissection after sequential chemoradiotherapy (SCRT) for advanced head and neck cancer and (2) compare survival parameters between those who underwent neck dissection and those who did not among those patients with a clinical complete response (cCR) in the neck after SCRT, thus assessing the benefit of neck dissection in patients with a cCR in the neck. DESIGN: Retrospective review with a mean follow-up of 3.5 years. SETTING: Regional cancer center. PATIENTS: The study population comprised 55 patients undergoing SCRT for advanced head and neck cancer with N2 or N3 neck disease. Three patients developed progressive disease and were excluded, and 28 patients underwent neck dissection. INTERVENTIONS: Patients were assessed by physical examination and radiographically after SCRT. MAIN OUTCOME MEASURES: Physical examination and radiographic assessments of residual neck disease were compared with pathologic findings in those patients who underwent neck dissection. Survival comparisons were made between patients with a cCR in the neck who underwent neck dissection and those who did not. RESULTS: Of 28 patients who underwent neck dissection, 8 had persistent pathologically positive nodal disease: 5 (45%) of 11 had N3 and 3 (18%) of 17 had N2 disease. Individual clinical neck assessments after SCRT were fairly predictive of a negative pathologic finding at neck dissection. The negative predictive values were physical examination (75%), computed tomography or magnetic resonance imaging (71%), and positron emission tomography (75%). However, when physical examination, imaging studies, and positron emission tomography all indicated a complete response, this accurately predicted a pCR on neck dissection. There appeared to be no improvement in survival parameters when a neck dissection was performed on patients with a cCR in the neck. CONCLUSIONS: Patients with N3 disease are at high risk for residual neck metastasis after SCRT. Patients with N2 disease can be assessed with physical examination, imaging studies, and positron emission tomography. If these all indicate a cCR, then neck dissection is likely not needed. Neck dissection did not appear to further improve survival parameters for patients with a cCR in the neck.

Adult↗
PubMed2006

Rituximab: a monoclonal antibody to CD20 used in the treatment of pemphigus vulgaris.

BACKGROUND: Rituximab is an anti-CD20 chimeric antibody that selectively targets B lymphocytes. Recently, it has been reported to be beneficial in treating pemphigus vulgaris. OBJECTIVE: Our aim was to review the English-language literature on the treatment of pemphigus vulgaris (PV) with rituximab and to determine its efficacy and influence on clinical outcome(s). MATERIAL AND METHODS: A retrospective review of the literature on the use of rituximab in the treatment of PV was conducted. Seventeen patients in 10 reports were described and their data were reviewed. RESULTS: The majority of patients received one course of rituximab along with conventional immunosuppressive therapy as concomitant therapy; 88% of the patients demonstrated improvement. More than half of the patients were followed up for more than 6 months after rituximab treatment; they appeared to be clinically disease free, but were still receiving conventional immunosuppressive therapy. Side effects in most patients were transient and infusion related. Serious infections occurred in 4 patients. One patient died. LIMITATIONS: The sample size of this study is small; there is no uniformity of data collection or measurement of key and critical indices, and follow-up was limited. CONCLUSION: Rituximab may be a promising agent in treatment of PV.

Antibodies↗
PubMed2006

Dysphagia after sequential chemoradiation therapy for advanced head and neck cancer.

OBJECTIVES: Assess impact of sequential chemoradiation therapy (SCRT) for advanced head and neck cancer (HNCA) on swallowing, nutrition, and quality of life. STUDY DESIGN: Prospective cohort study of 59 patients undergoing SCRT for advanced head and neck cancer. Follow-up median was 47.5 months. SETTING: Regional Cancer Center. RESULTS: Median time to gastrostomy tube removal was 21 weeks. Eighteen of 23 patients who underwent modified barium swallow demonstrated aspiration; none developed pneumonia. Six of 7 with pharyngoesophageal stricture underwent successful dilatation. Functional Assessment of Cancer Therapy-Head and Neck Scale questionnaires at median 6 months after treatment revealed "somewhat" satisfaction with swallowing. At the time of analysis, 97% have the gastronomy tube removed and take soft/regular diet. CONCLUSION: Early after treatment dysphagia adversely affected weight, modified barium swallow results, and quality of life. Diligent swallow therapy, and dilation as needed, allowed nearly all patients to have their gastronomy tubes removed and return to a soft/regular diet. SIGNIFICANCE: Dysphagia is significant after SCRT but generally slowly recovers 6 to 12 months after SCRT. EBM RATING: C-4.

Adult↗
PubMed2006

Chemoradiotherapy for adenoid cystic carcinoma: preliminary results of an organ sparing approach.

OBJECTIVES: A retrospective review of primary chemoradiotherapy (CRT) for adenoid cystic carcinoma (ACC) was performed to determine if CRT might be considered as an alternative to radiotherapy and/or definitive surgery. METHODS: All treatment-naive patients with ACC of the head and neck who were treated with definitive primary chemoradiotherapy using carboplatinum and paclitaxel at Dana-Farber Cancer Institute in 2000 through 2004 were identified. Information on site, stage, presenting symptoms, performance status, treatment, toxicity, and follow up were collected and tabulated for review. RESULTS: Five patients were identified with previously untreated ACC of the head and neck who received primary carboplatinum/paclitaxel CRT for unresectability or organ preservation. Patients had a median age of 41, 4 had primaries in the paranasal sinuses invading the base of skull and 1 had a transglottic laryngeal lesion. All patients completed a course of definitive chemoradiotherapy without treatment break. Grade 3 mucosal reactions developed during CRT in all patients. With a median follow-up of 36 months (range, 20-43) all patients have local regional control; 1 patient developed distant metastases at 7 months and is alive at 20 months. CONCLUSIONS: Preliminary data suggest that carboplatinum/paclitaxel based CRT for ACC provides local regional control and is a potential alternative to surgery or radiotherapy for patients with locally advanced ACC. Carboplatinum/paclitaxel based CRT warrants further study.

Adult↗
PubMed2006

Characterization of the opsonic and protective activity against Staphylococcus aureus of fully human monoclonal antibodies specific for the bacterial surface polysaccharide poly-N-acetylglucosamine.

Carbohydrate antigens are important targets of the immune system in clearing bacterial pathogens. Although the immune system almost exclusively uses antibodies in response to foreign carbohydrates, there is still much to learn about the role of different epitopes on the carbohydrate as targets of protective immunity. We examined the role of acetyl group-dependent and -independent epitopes on the staphylococcal surface of polysaccharide poly-N-acetylated glucosamine (PNAG) by use of human monoclonal antibodies (MAbs) specific for such epitopes. We utilized hybridoma technology to produce fully human immunoglobulin G2 (IgG2) MAbs from B cells of an individual post-Staphylococcus aureus infection and cloned the antibody variable regions to produce an IgG1 form of each original MAb. Specificity and functionality of the purified MAbs were tested in vitro using enzyme-linked immunosorbent assays, complement deposition, and opsonophagocytic assays. We found that a MAb (MAb F598) that bound the best to nonacetylated or backbone epitopes on PNAG had superior complement deposition and opsonophagocytic activity compared to two MAbs that bound optimally to PNAG that was expressed with a native level (>90%) of N-acetyl groups (MAbs F628 and F630). Protection of mice against lethality due to S. aureus strains Mn8 and Reynolds further showed that the backbone-specific MAb had optimal protective efficacy compared with the acetate-specific MAbs. These results provide evidence for the importance of epitope specificity in inducing the optimal protective antibody response to PNAG and indicate that MAbs to the deacetylated form of PNAG could be immunotherapeutic agents for preventing or treating staphylococcal infections.

Acetylglucosamine↗
PubMed2005

Phase I trial and pharmacokinetics of escalating doses of paclitaxel and concurrent hyperfractionated radiotherapy with or without amifostine in patients with advanced head and neck carcinoma.

BACKGROUND: Amifostine was developed to protect normal tissues from radiation exposure. The current study was undertaken to determine whether amifostine would allow the delivery of greater numbers of weekly paclitaxel treatments with concomitant, hyperfractionated radiotherapy in patients with advanced head and neck carcinoma. METHODS: Patients received radiation therapy twice daily using 1.6-gray (Gy) fractions up to a total of 70.4 Gy over an elapsed time of 6.5 weeks. All patients received paclitaxel 60 mg/m(2) once weekly starting on Day 1. The number of doses of paclitaxel was escalated from three to a maximum of six in groups of three patients. For the patients who received amifostine, a dose of 400 mg/m(2) was given intravenously over 15 minutes on Days 1-5, 8, 29-33, and 36. Patients underwent surgery for persistent tumor after radiotherapy. The plasma pharmacokinetics of paclitaxel were characterized during treatment with the first weekly dose to determine the effect of concurrently administered amifostine. RESULTS: Thirty-six patients were evaluable for this study. In the absence of amifostine, a maximum of four doses of paclitaxel were tolerated in combination with the radiotherapy. With amifostine, up to five doses of paclitaxel could be given. Generally, the treatment resulted in Grade 2 and 3 stomatitis. Overall, 69% of patients had a complete remission, and 29% had a partial remission. Both progression-free survival and overall survival were 66% at 30 months. Amifostine had no effect on the pharmacokinetics of paclitaxel. CONCLUSIONS: The administration of amifostine allowed the authors to give an additional dose of paclitaxel to patients who were undergoing hyperfractionated radiotherapy for head and neck carcinoma. This treatment regimen resulted in a high frequency of complete remissions and an excellent progression-free survival pattern without compromising the plasma kinetics of paclitaxel.

Amifostine↗
PubMed2005

Phase I study of gefitinib plus celecoxib in recurrent or metastatic squamous cell carcinoma of the head and neck.

PURPOSE: Effective and tolerable palliative treatments are needed for patients with incurable squamous cell carcinoma of the head and neck (SCCHN). Single-agent targeted therapies have limited activity in this setting. The feasibility of adding celecoxib to gefitinib for the treatment of incurable SCCHN is unknown. PATIENTS AND METHODS: Nineteen patients with unresectable recurrent locoregional and/or distant metastatic SCCHN with progressive disease after at least one prior chemotherapy or chemoradiotherapy regimen were enrolled onto this single-institution phase I study. Three dose levels were explored: (1) celecoxib 200 mg twice daily plus gefitinib 250 mg daily; (2) celecoxib 400 mg twice daily plus gefitinib 250 mg daily; and (3) celecoxib 400 mg twice daily plus gefitinib 500 mg daily. RESULTS: No dose-limiting toxicities were encountered at any dose level. The most common toxicities were acneiform rash, diarrhea, hand reaction, dyspepsia, and anemia. Four of 18 patients assessable for response (22%; 95% CI, 2% to 42%) achieved a confirmed partial response. CONCLUSION: The combination of gefitinib 500 mg daily plus celecoxib 400 mg twice daily is well-tolerated. The encouraging responses seen in this early study suggest further evaluation of epidermal growth factor receptor and cyclooxygenase-2 inhibitors in SCCHN is warranted.

Administration, Oral↗
PubMed2005

Dichotomy in cross-clade reactivity and neutralization by HIV-1 sera: Implications for active and passive immunotherapy.

The identification of broadly reactive and cross-clade neutralizing antibodies will facilitate the development of a more universally effective vaccine for human immunodeficiency virus (HIV). Antibodies in sera from individuals infected with Clade B HIV bind native primary viral isolates, and virus binding correlates with neutralization and stable clinical disease. In this study, we quantified cross-clade antibody reactivity and neutralization by Clades B and C sera. Primary viral isolates were captured by serum IgG bound to anti-human IgG and quantitated as p24 released by lysis of captured virus. Neutralization was determined using PHA-stimulated PBMC. Clade B antibodies reacted more frequently with Clade B R5 virus, but positive sera captured quantitatively more X4 virus than R5 and R5X4 virus. Clade B sera reacted less frequently and captured less Clade C virus than Clade B virus. Antibodies in Clade C sera captured Clades B and C isolates with equal frequency and quantity. There was no difference in neutralization of Clade B virus by either group of sera; however, Clade C sera neutralized Clade C virus, whereas Clade B sera were ineffective against Clade C virus. Thus, there are distinct differences in cross-clade reactivity of and neutralization by antibodies induced in response to Clade C infection compared to Clade B infection. Understanding antibody responses to native virions after Clade C infection and cross clade antibody behavior has implications for understanding pathogenesis and vaccine development.

AIDS Vaccines↗
PubMed2005

Serum concentrations of interleukin-8, vascular endothelial growth factor, and epidermal growth factor receptor in patients with squamous cell cancer of the head and neck.

Squamous cell cancer of the head and neck (SCCHN) is associated with production of pro-inflammatory and pro-angiogenic cytokines. We hypothesized that cytokine serum levels will correlate with tumor volume and aggressiveness. We investigated interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR) in SCCHN. The patient population consisted of normal and irradiated controls: patients with newly diagnosed SCCHN, and patients with recurrent or metastatic disease. Pretreatment sera were studied by ELISA. Serum IL-8 levels, as opposed to VEGF or EGFR, were consistently elevated in patients with recurrent or metastatic disease. The differences in mean serum IL-8, compared to controls, were significant (p=0.02). Serum levels of IL-8 are consistently elevated in patients with recurrent or metastatic SCCHN and elevated levels may correlate with advanced or aggressive disease. Further, more intensive, study of IL-8 as a biomarker in SCCHN is warranted.

Aged↗
PubMed2005

CD40 function in squamous cell cancer of the head and neck.

CD40 is expressed on basal keratinocytes and Squamous Cell Cancer of the Head and Neck (SCCHN) tumor cells in vivo and in vitro. CD40 ligation reduces proliferation of SCCHN cell lines and enhances EGFr mediated inhibition of proliferation. We investigated the mechanisms of CD40 function and EGFr cross-communication in SCCHN cell lines. CD40 ligation inhibited spontaneous and Fas-induced apoptosis. CD40 ligation specifically increased the secretion of IL-8, VEGF and PGE(2) but not IL-6, IL-10, FasL, GM-CSF, or TGFalpha. Co-ligation with EGFr further increased IL-8, VEGF and PGE(2) secretion. CD40 ligation also induced delayed activation and tyrosine phosphorylation of EGFr. CD40 induces secretion of specific proinflammatory and proangiogenic cytokines, inhibits spontaneous and Fas-induced apoptosis and increases EGFr phosphorylation. CD40 signaling may enhance the survival of SCCHN and tumor stroma.

Apoptosis↗
PubMed2005

Organ preservation and treatment toxicity with induction chemotherapy followed by radiation therapy or chemoradiation for advanced laryngeal cancer.

OBJECTIVES: The authors reviewed records of patients with advanced laryngeal cancer treated with induction chemotherapy (IC) and hyperfractionated radiation therapy (RT) or chemoradiation (CRT) to determine the rates of organ preservation and function. METHODS: A total of 29 patients with stage III (45%) and stage IV (55%) squamous cell carcinoma of the larynx (SCCL), were treated with IC and RT or CRT in 1 of 7 consecutive trials. Fifty-five percent had clinically node-positive disease. Fifty-five percent and 45% had T3 or T4 tumors, respectively. All received 3 cycles of platinum-based IC. Daily RT was given to 48%, twice-daily RT to 45%, and concomitant boost RT to 7%. CRT was carboplatin (28%) or docetaxel (28%). Those treated with twice-daily RT did not receive CRT. RESULTS: The median follow-up is 52 months. Overall survival is 66%. Relapse occurred in 12 patients (41%), and 6 underwent salvage laryngectomy (5 stage III, 1 stage IV). Fifty-nine percent of patients (17 of 29) are alive at last follow-up with an anatomically intact larynx, and 48% (14 of 29) are alive with a functional larynx. Of the 23 patients for whom detailed information on gastrostomy tube (g-tube) placement/removal was available, median time with g-tube was 12 months, and 15 of 23 patients (65%) had a g-tube for 6 months or more. Twenty-three of all 29 patients (79%) retained an anatomically intact larynx, but 7 of 23 (30%) never resumed their pretreatment organ function. The overall rate of functional organ preservation, regardless of survival, was 55% (16/29). The 7 of 29 patients (26%) who retained a nonfunctional larynx required permanent g-tube or were unable to return to pretreatment oral intake capability. Nine of 13 with T4 SCCL (69%) compared with 7 of 16 (44%) T3 SCCL retained a functional larynx. CONCLUSION: The rate of larynx preservation is high, but toxicity remains significant with IC followed by hyperfractionated RT or CRT in advanced laryngeal cancer. Half of all patients were alive, able to retain their larynx, and return to pretreatment function. Advanced stage was not an indicator of poor outcome.

Adult↗
PubMed2005

Structure of the Fab fragment of F105, a broadly reactive anti-human immunodeficiency virus (HIV) antibody that recognizes the CD4 binding site of HIV type 1 gp120.

We have determined the crystal structure of the Fab fragment from F105, a broadly reactive human antibody with limited potency that recognizes the CD4 binding site of gp120. The structure reveals an extended CDR H3 loop with a phenylalanine residue at the apex and shows a striking pattern of serine and tyrosine residues. Modeling the interaction between gp120 and F105 suggests that the phenylalanine may recognize the binding pocket of gp120 used by Phe(43) of CD4 and that numerous tyrosine and serine residues form hydrogen bonds with the main chain atoms of gp120. A comparison of the F105 structure to that of immunoglobulin G1 b12, a much more potent and broadly neutralizing antibody with an overlapping epitope, suggests similarities that contribute to the broad recognition of human immunodeficiency virus by both antibodies. While the putative epitope for F105 shows significant overlap with that predicted for b12, it appears to differ from the b12 epitope in extending across the interface between the inner and outer domains of gp120. In contrast, the CDR loops of b12 appear to interact predominantly with the outer domain of gp120. The difference between the predicted epitopes for b12 and F105 suggests that the unique potency of b12 may arise from its ability to avoid the interface between the inner and outer domains of gp120.

Amino Acid Sequence↗