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Quality of life (QOL) and functional status (FS) have become important outcome measures in cancer therapy. Valid and reliable instruments recently have been developed for examining QOL and FS in patients with head and neck (HN) cancer. The present study evaluated the relationships of QOL and FS to physical and psychological variables assumed to affect QOL and FS. Fifty patients were evaluated up to 6 years after HN cancer surgery using one general QOL instrument and three HN-specific instruments. Analysis of variance showed physical variables such as tumor site to be related to HN-specific scores, while psychosocial variables such as marital status were related to general QOL scores (P < or = .05). Several relationships were seen between physical or psychosocial variables and FS or QOL measures; however the relationships were not as strong or direct as expected. [ABSTRACT FROM AUTHOR]

Carcinoma of the parathyroid gland is a disease only rarely encountered in clinical practice. As most of these tumors retain the ability to manufacture active parathyroid hormone, most patients with the disease present with hypercalcemia, many times symptomatic. Since the tumor accounts for only 0.5% to 4.0% of cases of primary hyperparathyroidism, the diagnosis of parathyroid carcinoma may be unsuspected and delayed. The clinical index of suspicion should be elevated if there is a palpable neck mass, an exceptionally high serum calcium level, and/or recurrence of hypercalcemia following surgery. We review two patients with parathyroid carcinoma who presented with hypercalcemia. In both, the diagnosis of malignancy was made only after microscopic examination of the operative specimen. Surgery consisted of wide local excision in both cases; radiation therapy was administered in one. Postoperative disease-free status is now 23 and 37 months. One of the patients had a history of radiation therapy to the larynx 20 years prior to the development of parathyroid carcinoma. Also reviewed in this paper are the clinical and histopathologic criteria for making the diagnosis of parathyroid carcinoma and the therapeutic approaches and prognosis of this unusual tumor. [ABSTRACT FROM AUTHOR]

Objective: This study describes the relationship between health-related quality of life (HRQOL) and depression in patients following major surgery for head and neck cancer.Design: Cross-sectional study using medical chart review, patient interview, and test administration.Method: Fifty patients were evaluated 6 months to 6 years following surgery using one global HRQOL measure (The Functional Assessment of Cancer Therapy-General [FACT-G]); three disease-specific measures of HRQOL (the HN module of the FACT [FACT-HNS], The University of Washington Quality of Life Scale [UWQOL], and The Performance Status Scale for Head and Neck Cancer); and one measure of depression (The Beck Depression Inventory [BDI]).Results: The study population showed a high occurrence of depressive symptoms (22%). A negative correlation existed between the BDI and HRQOL as measured by the FACT-G (r = -0.49, P < .001) and the UWQOL (r = -0.44, P = .003). When somatic symptoms of depression were removed, the BDI remained correlated with HRQOL and was most highly correlated with the Emotional Well-Being (EWB) subscale of the FACT-G (r = -0.42, P = .003). There was no correlation between clinician judgments of EWB and any patient-rated measures of HRQOL or depression.Conclusions: Results demonstrate an inverse relationship between patient-reported HRQOL and depression. The lack of correlation between physician and patient ratings of HRQOL and EWB stresses the importance of obtaining patient ratings in addition to traditional clinician ratings when assessing outcomes. Finally, the multidimensional construction of the FACT with its specific subscales may make it a useful clinical tool for assessing patient status and augmenting patient interviews. [ABSTRACT FROM AUTHOR]

Factors that compete to establish heart failure (HF) are not completely known. In the last years the several technological improvements allowed us to deeply study the molecular and genetic aspects of this complex syndrome. This new approach to HF based on molecular biology new discoveries shows us more clearly the pathophysiological bases of this disease, and a future scenery where the genetics may be useful in the clinical practice, as screening of high risk populations, as well as in the diagnosis and therapy of underlying myocardial diseases. The purpose of this review was to analyse the molecular, genetic and epigenetic factors of HF. We described the molecular anatomy of the sarcomere and the pathogenesis of the heart muscle diseases, abandoning the previous monogenic theory for the concept of a polygenic disease. Different actors play a role to cause the illness by themselves, modifying the expression of the disease and, eventually, the prognosis of the patient.

Recombinant immunotoxins exhibit targeting and cytotoxic functions needed for cell-specific destruction. However, antitumor efficacy, safety, and pharmacokinetics of these therapeutics might be improved by further macromolecular engineering. SS1P is a recombinant anti-mesothelin immunotoxin in clinical trials in patients with mesothelin-expressing tumors. We have modified this immunotoxin using several PEGylation strategies employing releasable linkages between the protein and the PEG polymers, and observed superior performance of these bioconjugates when compared to similar PEG derivatives bearing permanent linkages to the polymers. PEGylated derivatives displayed markedly diminished cytotoxicity on cultured mesothelin-overexpressing A431-K5 cells; however, the releasable PEGylated immunotoxins exhibited increased antitumor activity in A431-K5 xenografts in mice, with a diminished animal toxicity. Most significantly, complete tumor regressions were achievable with single dose administration of the bioconjugates but not the native immunotoxin. Pharmacokinetic analysis of the releasable PEGylated derivatives in mice demonstrated an over 80-fold expansion of the area under the curve exposure of bioactive protein when compared to native immunotoxin. A correlation in degree of derivatization, release kinetics, and polymer size with potency was observed in vivo, whereas in vitro cytotoxicity was not predictive of efficacy in animal models. The potent antitumor efficacy of the releasable PEGylated mesothelin-targeted immunotoxins was not exhibited by similar untargeted PEG immunotoxins in this model. Since the bioconjugates can also exhibit the attributes of passive targeting via enhanced permeability and retention, this is the first demonstration of a pivotal role of active targeting for immunotoxin bioconjugate efficacy.

Arginine is an important metabolite in the normal function of several biological systems, and arginine deprivation has been investigated in animal models and human clinical trials for its effects on inhibition of tumor growth, angiogenesis, or nitric oxide synthesis. In order to design an optimal arginine-catabolizing enzyme bioconjugate, a novel recombinant arginine deiminase (ADI) from Mycoplasma arthritidis was prepared, and multi-PEGylated derivatives were examined for enzymatic and biochemical properties in vitro, as well as pharmacokinetic and pharmacodynamic behavior in rats and mice. ADI bioconjugates constructed with 12 kDa or 20 kDa monomethoxy-poly(ethylene glycol) polymers with linear succinimidyl carbonate linkers were investigated via intravenous, intramuscular, or subcutaneous administration in rodents. The selected PEG-ADI compounds have 22 +/- 2 PEG strands per protein dimer, providing an additional molecular mass of about 0.2-0.5 x 10(6) Da and prolonging the plasma mean residence time of the enzyme over 30-fold in mice. Prolonged plasma arginine deprivation was demonstrated with each injection route for these bioconjugates. Pharmacokinetic analysis employed parallel measurement of enzyme activity in bioassays and enzyme assays and demonstrated a correlation with the pharmacodynamic analysis of plasma arginine concentrations. Either ADI bioconjugate depressed plasma arginine to undetectable levels for 10 days when administered intravenously at 5 IU per mouse, while the subcutaneous and intramuscular routes exhibited only slightly reduced potency. Both bioconjugates exhibited potent growth inhibition of several cultured tumor lines that are deficient in the anabolic enzyme, argininosuccinate synthetase. Investigations of structure-activity optimization for PEGylated ADI compounds revealed a benefit to constraining the PEG size and number of attachments to both conserve catabolic activity and streamline manufacturing of the experimental therapeutics. Specifically, ADI with either 12 kDa or 20 kDa PEG attachments on 33% of the primary amines retained about 60% or 48% of enzyme activity, respectively; the Km and pH profiles were nearly unchanged; IC50 values were diminished by less than 30%; while stability studies demonstrated full retention of activity at 4 degrees C for 5 months. A comparison of the enzymatic properties of a second ADI from Pseudomonas putida illustrated the superior characteristics of the M. arthritidis ADI enzyme.

Recombinant interferon-beta-1b (IFN-beta-1b) is used clinically in the treatment of multiple sclerosis. In common with many biological ligands, IFN-beta-1b exhibits a relatively short serum half-life, and bioavailability may be further diminished by neutralizing antibodies. While PEGylation is an approach commonly employed to increase the blood residency time of protein therapeutics, there is a further requisite for molecular engineering approaches to also address the stability, solubility, aggregation, immunogenicity and in vivo exposure of therapeutic proteins. We investigated these five parameters of recombinant human IFN-beta-1b in over 20 site-selective mono-PEGylated or multi-PEGylated IFN-beta-1b bioconjugates. Primary amines were modified by single or multiple attachments of poly(ethylene glycol), either site-specifically at the N-terminus, or randomly on the 11 lysines. In two alternate approaches, site-directed mutagenesis was independently employed in the construction of designed IFN-beta-1b variants containing either a single free cysteine or lysine for site-specific PEGylation. Optimization of conjugate preparation with 12 kDa, 20 kDa, 30 kDa, and 40 kDa amine-selective PEG polymers was achieved, and a comparison of the structural and functional properties of the IFN-beta-1b proteins and their PEGylated counterparts was conducted. Peptide mapping and MALDI-TOF mass spectrometric analysis confirmed the attachment sites of the PEG polymer. Independent biochemical and bioactivity analyses, including antiviral and antiproliferation bioassays, circular dichroism, capillary electrophoresis, flow cytometric profiling, reversed phase and size exclusion HPLC, and immunoassays demonstrated that the functional activities of the designed IFN-beta-1b conjugates were maintained, while the formation of soluble or insoluble aggregates of IFN-beta-1b was ameliorated. Immunogenicity and pharmacokinetic studies of selected PEGylated IFN-beta-1b compounds in mice and rats demonstrated both diminished IgG responses, and over 100-fold expanded AUC exposure relative to the unmodified protein. The results demonstrate the capacity of this macromolecular engineering strategy to address both pharmacological and formulation challenges for a highly hydrophobic, aggregation-prone protein. The properties of a lead mono-PEGylated candidate, 40 kDa PEG2-IFN-beta-1b, were further investigated in formulation optimization and biological studies.

Blindness is a devastating complication of bilateral radical neck dissection. To our knowledge, it has been reported in the literature only 12 times. Although the cause is still controversial, many common factors have been identified. We present a case of blindness after bilateral neck dissection and discuss the perioperative circumstances and the possible causes. We also compare and contrast other cases described in the literature and suggest methods in which this complication can be prevented.

In a sample of 578 children assessed in kindergarten through the eighth grade, we used growth modeling to determine the basic developmental trajectories of mother-reported and teacher-reported externalizing and internalizing behaviors for three physical maltreatment groups of children-early-harmed (prior to age 5 years), later-harmed (age 5 years and over), and nonharmed--controlling for SES and gender. Results demonstrated that the earlier children experienced harsh physical treatment by significant adults, the more likely they were to experience adjustment problems in early adolescence. Over multiple domains, early physical maltreatment was related to more negative sequelae than the same type of maltreatment occurring at later periods. In addition, the fitted growth models revealed that the early-harmed group exhibited someswhat higher initial levels of teacher-reported externalizing problems in kindergarten and significantly different rates of change in these problem behaviors than other children, as reported by mothers over the 9 years of this study. The early-harmed children were also seen by teachers, in kindergarten, as exhibiting higher levels of internalizing behaviors. The later-harmed children were seen by their teachers as increasing their externalizing problem behaviors more rapidly over the 9 years than did the early- or nonharmed children. These findings indicate that the timing of maltreatment is a salient factor in examining the developmental effects of physical harm.

Radionuclide scanning for hyperparathyroidism is an accurate cost-effective preoperative test that can provide the basis for more effective surgery.

Surgery for correction of primary hyperparathyroidism utilizing a standard bilateral neck exploration has a success rate of approximately 90 to 95%. With the inception of pre-operative localization studies that were 90% accurate in localizing the diseased gland, the concept arose that a unilateral exploration could be as successful as a bilateral exploration. Bilateral exploration of the neck for hyperparathyroidism exposes the patient to a greater potential of morbidity for hypoparathyroidism and recurrent laryngeal nerve injury. It is our feeling based on personal experience that unilateral parathyroidectomy in selective cases can be as successful as the bilateral operation and be more cost effective, saving over $1,100 (U.S.) per case.

Reconstructive challenges engendered by skull base surgery are critical determinants of outcome. A novel nonpenetrating, arcuate-legged clip has proven to be both technically and biologically effective for management of these difficult closures. Clips have facilitated reconstructions associated with the surgical management of eight skull base cases: leiomyosarcoma of the orbit, middle fossa, ptyergopalatine fossa, two meningiomas (petrotentorial, cavernous sinus), vagus nerve paraganglioma, complex traumatic orbital dural tear, and one basilar and two vertebral artery aneurysms.

In a review of thyroid surgery performed at Loma Linda University and its affiliated hospitals during the past 20 years, 254 (26%) of the thyroid surgery patients had thyroid carcinoma. The majority of these patients underwent total thyroidectomy and received postoperative radioactive iodine. At the present time, there is considerable disagreement in the literature regarding the extent of treatment needed for what, in many cases, is a low-grade malignancy. In the present series, there are a significant number of patients with extensive disease in which aggressive treatment is warranted to improve the chance of cure. We believe that total thyroidectomy with central node dissection is the minimum surgical procedure required.

Currently, among otolaryngologists, much attention is focused on the surgical management of paranasal sinus disease. However, transantral sphenoethmoidectomy is rarely mentioned in the literature of the past several decades. We reviewed a consecutive series of 98 patients over a 12-year period who underwent transantral sphenoethmoidectomy in the treatment of severe chronic hyperplastic pansinusitis. The major and minor complications encountered are tabulated, as are the clinical outcomes. A description of the operative technique is followed by a discussion of the indications for this approach. We believe transantral sphenoethmoidectomy has a useful place in modern paranasal sinus surgery.

Primary hyperparathyroidism can be caused by a solitary parathyroid adenoma and sometimes by hyperplastic parathyroid glands, multiple adenomas, or carcinoma. In the majority of patients, the diagnosis is made tentatively by chemistry profiles that show elevated serum calcium. It is confirmed by repeated serum calcium values and PTH determination. The parathyroid abnormality, if an adenoma, can usually be localized preoperatively by thallium-technetium scan, ultrasound, or computed tomography. In the case of persistent disease with hypercalcemia, an angiogram with selective venous sampling for PTH is helpful. At exploration, both sides of the neck may need exploration. A unilateral procedure may be sufficient, if the preoperative localization tests are confirmatory and if biopsy of another "normal" gland shows normal histologic findings. During the postoperative period, suction drains will lessen the likelihood of hematoma formation and serum calcium levels are monitored for the first 3 to 5 days. Symptomatic patients with low calcium levels receive intravenous and oral calcium supplements until values are brought to the low-normal range. Supplements are tapered as the calcium in the serum rises. The majority of patients who undergo parathyroid surgery will benefit both symptomatically and metabolically.

A ten-year study of all patients undergoing surgical treatment for hyperparathyroidism at Loma Linda University is presented. Clinical characteristics, laboratory analysis, differential diagnosis, associated diseases, operative techniques, and postoperative management of potential complications are evaluated. Some patients with secondary hyperparathyroidism underwent autotransplantation with good results; this technique is discussed. An approach is detailed that is successful in maintaining euparathyroidism.