Lung cancer: Premalignant biology and medical prevention.

Lung cancer (both adenocarcinoma and squamous cell) progress through a series of pre-malignant histologic changes before the development of invasive disease. Each of these carcinogenic cascades is defined by genetic and epigenetic alterations in pulmonary epithelial cells. Additionally, alterations in the immune response, progenitor cell function, mutational burden, and microenvironmental mediated survival of mutated clones contribute to the risk of pre-malignant lesions progressing to cancer. Medical preventions studies have been completed and current and future trials are informed by the improved understanding of pre-malignancy. This will lead to precision chemoprevention trials based on lesional biology and histologic characteristics.

Prostacyclin reverses the cigarette smoke-induced decrease in pulmonary Frizzled 9 expression through miR-31.

Half of lung cancers are diagnosed in former smokers, leading to a significant treatment burden in this population. Chemoprevention in former smokers using the prostacyclin analogue iloprost reduces endobronchial dysplasia, a premalignant lung lesion. Iloprost requires the presence of the WNT receptor Frizzled 9 (Fzd9) for inhibition of transformed growth in vitro. To investigate the relationship between iloprost, cigarette smoke, and Fzd9 expression, we used human samples, mouse models, and in vitro studies. Fzd9 expression was low in human lung tumors and in progressive dysplasias. In mouse models and in vitro studies, tobacco smoke carcinogens reduced expression of Fzd9 while prostacyclin maintained or increased expression. Expression of miR-31 repressed Fzd9 expression, which was abrogated by prostacyclin. We propose a model where cigarette smoke exposure increases miR-31 expression, which leads to decreased Fzd9 expression and prevents response to iloprost. When smoke is removed miR-31 is reduced, prostacyclin can increase Fzd9 expression, and progression of dysplasia is inhibited. Fzd9 and miR-31 are candidate biomarkers for precision application of iloprost and monitoring of treatment progress. As we continue to investigate the mechanisms of prostacyclin chemoprevention and identify biomarkers for its use, we will facilitate clinical trials and speed implementation of this valuable prevention approach.

Angiogenic squamous dysplasia in bronchi of individuals at high risk for lung cancer.

Lung carcinogenesis is assumed to be a multistep process, but detailed understanding of the sequential morphological and molecular changes preceding invasive lung cancer remains elusive. To better understand early lung carcinogenesis, we initiated a program of fluorescence bronchoscopy in smokers at high risk for lung cancer. In the bronchial biopsies from these subjects, we observed a unique lesion consisting of capillary blood vessels closely juxtaposed to and projecting into metaplastic or dysplastic squamous bronchial epithelium, angiogenic squamous dysplasia (ASD). Serial sections of the capillary projections confirmed that they represent intramucosal capillary loops. Microvessel density in ASD was elevated in comparison to normal mucosa (P = 0.0003) but not in comparison to other forms of hyperplasia or dysplasia. ASD thus represents a qualitatively distinct form of angiogenesis in which there is architectural rearrangement of the capillary microvasculature. Genetic analysis of surface epithelium in a random subset of lesions revealed loss of heterozygosity at chromosome 3p in 53% of ASD lesions. No confirmed p53 mutations were identified. Compared with normal epithelium, proliferative activity was markedly elevated in ASD lesions. ASD occurred in 54 of 158 (34%) high-risk smokers without carcinoma and in 6 of 10 patients with squamous carcinoma who underwent fluorescence bronchoscopy. One early-stage invasive carcinoma was noteworthy for the occurrence of ASD juxtaposed to invasive tumor. Seventy-seven (59%) of the ASD lesions were detected by abnormal fluorescence alone. Twenty bronchial sites (11 patients) were rebiopsied 1 year after the initial diagnosis. At nine (45%) of these sites, the lesion was found to persist. The lesion was not present in biopsies from 16 normal nonsmoker control subjects. The presence of this lesion in high-risk smokers suggests that aberrant patterns of microvascularization may occur at an early stage of bronchial carcinogenesis.

Utilization of renal slices to evaluate the efficacy of chelating agents for removing mercury from the kidney.

Mercury is an environmental contaminant that preferentially accumulates in the kidney. It has been previously shown using proton-induced X-ray emission analysis that mercury (HgCl2) accumulated in precision-cut rabbit renal cortical slices. In this study, the efficacy of seven chelating agents for the removal of Hg from renal slices has been examined. Rabbits were injected with HgCl2 (10 mg/kg) and 3 h later kidneys were sliced, or renal slices were exposed in vitro to a mildly toxic concentration of HgCl2 (5 x 10(-5)M, 4 h). The slices were then treated in vitro with 10 mM concentrations of EDTA, lipoic acid (LA), penicillamine (PA), glutathione (GSH), 1,4-dithiothreitol (DTT), DMSA, or DMPS. DMPS proved to be the most effective in mobilizing Hg from in vivo or in vitro HgCl2-exposed renal tissue ( > 85% of control after 3 h incubation). Relative efficacies for the seven agents were DMPS > DMSA, PA > DTT, GSH > LA, EDTA. The use of renal slices appears to be a useful in vitro tool for assessing the efficacy of chelating agents on mobilizing accumulated Hg from renal tissue.

Complications of mechanical ventilation. A bedside approach.

Instead of cataloging complications reported to occur during mechanical ventilation, the authors have discussed the potential causes for several common scenarios in the management of ventilated patients. These include the new development of hypotension, acute respiratory distress (fighting the ventilator), repeated sounding of the ventilator's high-pressure alarm, hypoxemia, blood from the endotracheal tube, and the problem of diagnosing VAP. In the course of considering likely explanations for this group of circumstances for which the clinician is consulted or called to the bedside, virtually all reported ventilator-associated complications must be discussed. This new approach to an important aspect of ICU care may aid in clinical problem-solving and reduce the likelihood that a diagnosis will be missed or inappropriate measures taken in the absence of a systematic, pathophysiology-based approach.

Microanalytic acoustical voice characteristics of near-total laryngectomy.

Limited acoustic data are available describing vocal characteristics of individuals after near-total laryngectomy. Computer-based acoustic analyses (FO, jitter, shimmer, signal-to-noise ratio) were performed on vowel samples produced by 20 speakers who underwent near-total laryngectomy. On the basis of data obtained, the subjects who had undergone near-total laryngectomy demonstrated (1) higher than normal and more variable modal fundamental frequency values for sustained vowels; (2) increased frequency (jitter) and amplitude (shimmer) perturbation; and (3) decreased spectral noise (signal-to-noise) components. In addition, speakers who had undergone near-total laryngectomy showed an increased percentage of unvoiced sound production during their vowel productions. The large variability and general aperiodicity of the phonatory signal during vowel production suggests an ineffective laryngeal valving system with overcompensation in attempts to generate effective voice. These findings have implications for designing behavioral therapy programs to improve voice quality in speakers who receive conservation laryngectomy procedures for treatment of laryngeal carcinoma.

Quality of life after surgical treatment of cancer of the larynx.

The purpose of the study was to assess the quality of life of patients after surgical treatment for cancer of the larynx. Three groups of patients were identified according to surgical treatment: total laryngectomy, 111 patients; near-total laryngectomy, 38 patients; and partial laryngectomy, 23 patients. The impact of successful surgical treatment on their life roles was analyzed in terms of work, activities, familial and spousal relationships, sexuality, and psychologic features such as stress and anxiety. Two questionnaires were used; the Psychosocial Adjustment to Illness Scale (PAIS) and the Mayo Clinic Postlaryngectomy Questionnaire. With the PAIS questionnaire, no difference was found in role adjustment between the total laryngectomy and near-total laryngectomy groups, with one exception. In the work domain, the total laryngectomy patients who were working had better adjustment than the near-total laryngectomy patients. The overall adjustment of both groups was less favorable than that of a comparison group of patients with nonlaryngeal cancer. The patients who had the classic conservation operations adjusted in all domains more favorably than the patients with permanent tracheostomas. The partial operation patients adjusted better than the nonlaryngeal cancer patients. We conclude that the stoma has a negative impact on adjustment postoperatively and that it may have a more serious impact on life adjustment than voice alteration. Further investigation and standardization of measurement tools are needed.

Interaction of metals during their uptake and accumulation in rabbit renal cortical slices.

The uptake and accumulation of metals occurs in the kidney, which is a key site for interaction between metal nephrotoxicants. The uptake/accumulation and interaction of CdCl2, HgCl2, K2Cr2O7, and NaAsO2 was examined in precision-cut rabbit renal cortical slices. Slices were incubated with 10(-6) to 10(-3) M of a single metal toxicant or combinations of metal toxicants for 12 hr in DME-F12 media. Slices were blotted and sandwiched between two mylar films stretched across XRF sample cups. Quantitation of the metal in the slices was performed by proton-induced X-ray emission analysis (PIXE). The uptake of the metals was rapid, often reaching a maximum between 3 to 6 hr; the accumulation of Hg was highest, followed in order by Cd, Cr, and As. When two metals were present together, substantial alterations were observed in the uptake of the metals in the slices. HgCl2 hindered the uptake of K2Cr2O7, NaAsO2, CdCl2 (in this order), whereas these metals facilitated the uptake of HgCl2. However, a decreased uptake of both metals was often noted after exposure to other combinations of metals. PIXE analysis of metal content in slices is attractive since all elements (atomic number > 20) can be determined simultaneously. This information will be particularly useful in studying potential toxic interactions.

Effects of halothane and other volatile anaesthetics on protein synthesis and secretion in guinea pig liver slices.

We have investigated the effect of volatile anaesthetics on protein synthesis and secretion in Hartley male guinea pig liver slices. The slices (250-300 microns thick) were incubated in sealed roller vials containing Krebs-Henseleit buffer at 37 degrees C under 95% oxygen. Volatile anaesthetics were vaporized in the vials to produce constant concentrations in the medium. Halothane 1-2.1 mmol litre-1 produced a concentration-related decrease in protein synthesis (3H-leucine incorporation) and secretion. Deuterated halothane (d-halothane), which is less biotransformed, was less inhibiting than halothane: uptake of the 3H-leucine was not affected but its incorporation into the nascent peptide was inhibited. Enflurane 2.2 mmol litre-1, isoflurane 2.2 mmol litre-1 and sevoflurane 2.1 mmol litre-1 also inhibited protein synthesis, but to a lesser extent than halothane and d-halothane. We conclude that alterations in protein synthesis and secretion are an early and sensitive indicator of cellular injury by volatile anaesthetics in liver slices.

"Tuning in" and "fading out": performance of aphasic patients on ordered PICA subtests.

Performance of 182 aphasic patients was examined on 11 PICA subtests for which the order of presentation of items is specified in an attempt to determine possible "tuning in" and "fading out" behavior. Results indicate that these phenomena occur as measurable patterns, which are to some degree dependent on the severity of aphasia as measured by each patient's overall PICA percentile.

Prediction of PICA overall score by short versions of the test.

Two short versions (SPICAs) of the Porch Index of Communicative Ability (PICA) were developed and investigated, with specific attention to their ability to predict standard PICA overall scores of patients with aphasia. Ninety-three patients were administered three versions of the test in randomized order. Results indicate that SPICAs predict overall scores by standard administration at acceptable confidence levels in approximately one-third of the time required for the administration of the standard PICA.

Tongue strength. Part II: in artificial alaryngeal speech.

Tongue strength does not appear to be reduced in proficient esophageal speakers. However, no data exist on tongue strength for laryngectomized subjects who have not developed esophageal speech. Anterior and lateral tongue strength measures were obtained from 13 laryngectomized subjects who used an artificial larynx and 15 normal subjects by means of a pressure transducer and recording device. The results indicated that laryngectomized subjects had significantly weaker tongues in two of three directions measured. It was concluded that laryngectomy may affect tongue strength, but that the method of alaryngeal speech utilized postoperatively influences the return to normal.

Tongue strength Part I: Following total laryngectomy.

Surgical repositioning of the genioglossus muscle, as in total laryngectomy, may have an adverse effect on the protrusive strength of the tongue. To test this premise, anterior and lateral tongue strength measures were obtained from 10 laryngectomized and 15 normal subjects by means of a pressure transducer and recording device. The results indicated no significant difference between laryngectomized and normal subjects on tongue strength measures. Further, all laryngectomized subjects were judged to have good to excellent esophageal speech. It was concluded that laryngectomy does not adversely affect the major musculature concerned with protrusive tongue strength for proficient esophageal speakers.

Presurgical counseling needs of laryngectomaes: a survey of 78 patients.

Studies of candidated for laryngectomy have revealed a wide range of misconceptions about this surgery and its siquellae. To evalute current preoperative counseling practices, counseling deficits, and needs as perceived by the patient and his family, we surveyed all persons who had undergone laryngectomy at this institution since January 1974. The data indicated that present presurgical counseling practices are inadequate for most patients. There was considerable discrepancy between the actual counseling the patients received and what they considered ideal. For example, most received preoperative information only from their surgeons. Yet many indicated that laryngectomy candidates should be counseled by nurses, speech pathologists, recovered laryngectomees, and others. Almost all reported that the spouse should be present during counseling. Many survey respondents indicated that printed materials and/or audiovisual programs would also be desirable.

Phonemic behavior of aphasic subjects without dysarthria or apraxia of speech.

Thirty adult aphasic subjects without apraxia of speech or dysarthria were tested for their ability to produce phonemes in single test words and in spontaneous contextual speech. Results indicated that 75% of the total phonemic errors were due to a whole-word phenomenon apparently associated with faulty processing of the word rather than faulty production of the phoneme. True phonemic errors comprised 25% of the total errors or about 2% of all responses. Phoneme substitutions were by far the most frequent error (61%). Of the 30 subjects, 28 made no phonemic errors in spontaneous contextual speech. Aphasic behavior is not characterized by significant breakdown of articulatory performance. Observed patterns of error do not clearly support a phonemic regression hypothesis.

Practicality of shortening the Porch Index of Communicative Ability.

This study investigated the practicality of developing short forms of the Porch Index of Communicative Ability (PICA). Stepwise regression procedures were performed using data from 222 complete administrations of the PICA to determine the accuracy of prediction of overall scores on the basis of data from either fewer subtests or fewer items. Results indicated that the PICA is highly redundant and that it may be possible to develop useful shorter forms of it.