Ultrase MT12 and Ultrase MT20 in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: safety and efficacy.

BACKGROUND: Cystic fibrosis causes exocrine pancreatic insufficiency, leading to malabsorption. Supplemental pancreatic enzyme therapy alleviates the concomitant malnutrition experienced by cystic fibrosis patients. It is recognized that patients experience variations in clinical response to different brands of enzymes. This has prompted the US Food and Drug Administration to require that enzyme supplements be subjected to New Drug Applications. AIM: To investigate the safety and efficacy of supplemental pancreatic enzyme therapy in cystic fibrosis subjects. METHODS: We compared two doses of one formulation of enteric-coated pancreatic enzymes: Ultrase MT12 (12,000 lipase units per capsule) and Ultrase MT20 (20,000 lipase units per capsule), to placebo in two separate safety and efficacy studies. RESULTS: Mean total fat, protein and carbohydrate intake did not differ significantly between the groups. A significant difference in both fat and protein absorption occurred with the enzyme therapy groups. The Ultrase MT12 and Ultrase MT20 groups experienced a mean fat and protein absorption 79.4% and 83.8%, and 87.3% and 88.6%, respectively. No adverse events related to study drug were reported. CONCLUSIONS: This study further supports the use of enzymes to treat pancreatic insufficiency in cystic fibrosis. Excellent fat and protein absorption was achieved with minimal adverse events and safe doses.

The pharmacokinetics of colistin in patients with cystic fibrosis.

The safety and pharmacokinetics of colistin were determined after first dose (n = 30) and again under steady-state conditions (n = 27) in 31 patients with cystic fibrosis receiving the drug as a component of their treatment for an acute pulmonary exacerbation of their disease. Patients ranged in age from 14 to 53 years and received colistin for 6 to 35 days. Each patient was started on colistin 5 to 7 mg/kg/day administered intravenously in three equally divided doses. Elimination half-life (t1/2), mean residence time (MRT), steady-state volume of distribution (Vdss), total body clearance (Cl), and renal clearance (Clr) after first-dose administration averaged 3.4 hours, 4.4 hours, 0.09 l/kg, and 0.35 and 0.24 ml/min/kg, respectively. No differences in colistin disposition characteristics between first-dose and steady-state evaluations were observed. Sputum sampling was incomplete and confounded by previous aerosol administration but revealed colistin concentrations that markedly exceeded observed plasma concentrations. Twenty-one patients experienced one or more side effects attributed to colistin administration. The most common reactions involved reversible neurologic manifestations, including oral and perioral paresthesias (n = 16), headache (n = 5), and lower limb weakness (n = 5). All of these apparent colistin-induced neurologic adverse effects, though bothersome, were benign and reversible. Intermittent proteinuria was observed on urinalysis in 14 patients, and 1 patient developed reversible, colistin-induced nephrotoxicity. No relationship between the occurrence of any colistin-associated adverse effect and plasma colistin concentration or colistin pharmacokinetic parameter estimate was observed. These data provide no basis for routine monitoring of colistin plasma concentrations to guide dosing for patient safety and suggest slow upward dose titration to minimize the incidence and severity of associated side effects.

Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types.

One thousand consecutive cases of surgically proven endometriosis were reviewed to evaluate the frequency and types of pelvic cancers that were associated with ovarian and extraovarian endometriosis. The frequency and types of histologic abnormalities present in the eutopic endometrium when cancers were noted in endometriosis were also evaluated. In the large subset of cases for which the authors were the primary pathologists and all foci of endometriosis were recorded, the frequency of malignancy was 10.8%. In contrast, the frequency was only 3.2% in cases diagnosed by others previously in our institution. Cancers were more commonly found in ovaries when endometriosis was present in that ovary (5%) compared to when endometriosis was present at other sites (1%). Clear cell and endometrioid carcinomas were the malignancies most commonly seen in ovaries containing endometriosis, while clear cell adenocarcinoma and adenosarcoma were most commonly seen in conjunction with extraovarian endometriosis. The association of endometriosis with endometrioid and clear cell carcinoma was much stronger than that of serous and mucinous tumors (p < .01). Concurrent endometrial pathology was commonly seen in cases of malignant transformation of endometriosis (32% of cases).

Significance of lymphoglandular bodies in bone marrow aspiration smears.

The presence of lymphoglandular bodies (LGB) or Söderström bodies is often stated to be a feature of lymphoid processes. In our experience, LGB are typically identified in B-cell processes but not in T-cell lymphomas or myeloid leukemias. We reviewed 136 bone marrow aspirate smears. The number of LGB per five high-power fields was counted, and median counts for B-cell processes, non-B-cell processes, myeloid leukemias, and T-cell malignancies were obtained and compared by the Wilcoxon rank sum test. Bone marrow aspirate smears involved with B-cell malignancies contained a median of 30 (range, 1-250) LGB per five high-power fields. Compared to myeloid leukemias (median, 11; range, 1-253) and T-cell malignancies (median, 7; range, 0-41), the differences were statistically significant (P < 0.001 and P = 0.01, respectively). While lymphoglandular bodies can be seen in a variety of malignant hematopoietic and nonhematopoietic disorders, they are found in significantly greater numbers in B-cell malignancies.

Diagnosis of hematopoietic processes by fine-needle aspiration in conjunction with flow cytometry: A review of 127 cases.

Although fine-needle aspiration (FNA) is accepted as the method of choice for the initial evaluation of lymph nodes for metastatic carcinomas, its utility as the initial diagnostic procedure for hematopoietic processes is less established. We review our experience over a 3-year period with 127 FNA cases accompanied by flow cytometric (FC) analysis from 117 patients. Fifty cases had subsequent histologic examination. A hematopoietic process was identified in 85 cases, a reactive process in 27 cases, and a nonhematopoietic process in 15 cases. All non-Hodgkin lymphomas (NHL) were B-cell processes except for one T-cell lymphoma. By FNA/FC, 44 NHL had sufficient findings to be subtyped; of these, 27 had subsequent histologic examination. The correlation between the FNA/FC and histologic classification in these cases of NHL was 100%. One case was insufficient for diagnosis by FNA and six cases were inadequate for FC. We conclude that FNA in conjunction with FC can be used as the initial diagnostic approach for both primary and recurrent hematopoietic processes.

Cytomorphologic features of sebaceous carcinoma on fine needle aspiration.

OBJECTIVE: To describe three cases of sebaceous carcinoma metastatic to regional lymph nodes diagnosed by fine needle aspiration (FNA). STUDY DESIGN: FNA was performed using standard techniques. A portion of each specimen was stained with Diff-Quick (Dade, Miami, Florida, U.S.A.); another portion was fixed in 95% ethanol and stained with a modified Papanicolaou stain or fixed in formalin and stained with hematoxylin and eosin. RESULTS: All carcinomas were moderately cellular, with primarily irregular cell clusters. The cytoplasm was finely reticular and contained variable numbers of small vaculoes. Nuclei were centrally located and pleomorphic and contained coarse chromatin. Variably sized but often large nucleoli were seen. Mitotic figures were easily identified. CONCLUSION: Sebaceous carcinoma is a rare but cytologically distinct neoplasm. It frequently metastasizes to regional lymph nodes and may then appear as a mass amenable to FNA. Aspiration cytologists, particularly those who aspirate head and neck lesions, should be familiar with the distinct features of this neoplasm.

A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency.

OBJECTIVE: The safety and efficacy of Minimicrospheres, which are enteric-coated, delayed-release pancrelipase capsules, on fat absorption in pediatric/adolescent and adult cystic fibrosis (CF) patients was assessed. Exocrine pancreatic insufficiency, common in CF patients, causes steatorrhea due to insufficient release of pancreatic enzymes. METHODS: In the open-label phase, 97 CF patients with pancreatic insufficiency and steatorrhea were stabilized on a high-fat diet and administered pancrelipase. Seventy-four patients with >80% coefficient of fat absorption received placebo or pancrelipase in the double-blind phase. Fat intake and excretion, stool frequency and consistency, and clinical global improvement were recorded. RESULTS: Average daily fat intake was comparable between treatment groups within each age group (adults vs pediatric/adolescent), but placebo patients had a significant (p < 0.001) mean decrease in coefficient of fat absorption (adult, 36.9 percentage points; pediatric/adolescent, 34.9 percentage points) from open-label to double-blind treatment compared to pancrelipase patients (adult, 2 percentage points; pediatric/adolescent, 3.25 percentage points); this difference was caused by a greater (p < or = 0.001) increase in mean fecal fat excretion (grams per day) in the placebo groups compared to pancrelipase groups (adult: 61.9 vs 2.3; pediatric/adolescent: 45.4 vs 4.1). Change in mean stool frequency from open-label to double-blind phases was significantly different (p < or = 0.002) between treatment groups, with increases in placebo groups and no difference (adult) or decrease (pediatric/adolescent) in pancrelipase groups. Pancrelipase patients' stool consistency remained about the same from open-label to double-blind. Placebo patients' stool consistency decreased (became softer) from open-label pancrelipase to double-blind placebo. Clinical global improvement data showed that > or =83% of pancrelipase patients improved or remained unchanged. CONCLUSIONS: Enteric-coated, delayed-release (Minimicrospheres) pancrelipase capsules are an effective treatment for steatorrhea associated with pancreatic insufficiency in patients with cystic fibrosis.

Paraneoplastic limbic encephalitis associated with small cell carcinoma of the prostate.

A 76-year-old man with primary small cell carcinoma of the prostate died after a subacute illness marked by memory loss and truncal ataxia Post-mortem examination of the central nervous system was consistent with limbic encephalitis and cerebellar degeneration. Although limbic encephalitis is a known complication of small cell carcinoma of the lung, this seems to be the first reported case of limbic encephalitis associated with small cell carcinoma of the prostate. Implications with respect to diagnosis and therapy are discussed.

Timing of referral for lung transplantation for cystic fibrosis: overemphasis on FEV1 may adversely affect overall survival.

STUDY OBJECTIVES: (1) Report our experience with referral for lung transplantation. (2) Review survival in cvstic fibrosis (CF) patients without lung transplantation after FEV1 remains < 30% predicted for 1 years. DESIGN: Retrospective review. SETTING: A university hospital CF center. PATIENTS: (1) Forty-five patients referred for lung transplantation evaluation, and (2) 178 patients without Burkholderia sp infection, with the above FEVl criterion. MAIN OUTCOME MEASURE: Survival. MEASUREMENTS AND RESULTS: (1) One- and 2-year survival after transplantation was 55% and 45%, respectively. However, among patients without transplants with FEVl < 30% predicted, median survival, 1986 to 1990, ie, before the transplant era, was 4.6 years with 25% living > 9 years (before 1986, 25% lived > 6 vears). (2) Survival after transplantation was not correlated to any of the following: age, sex, genotype, FEVI percent predicted, insulin-dependent diabetes mellitus, or with waiting time before transplantation, and did not seem to be correlated to serum bicarbonate or percent ideal body weight. Four of five patients already infected with Burkholderia species died within 5 months of transplantation; the fifth died at 17 months. All five died of pulmonary or extrapulmonarv infection with Burkholderia species CONCLUSIONS: Use of FEV! < 30% predicted to automatically establish transplantation eligibility could lead to decreased overall survival for CF patients. Referral for evaluation and transplantation should also be based on oxygen requirement, rate of deterioration, respiratory microbiology, quality of life, frequency of IV antibiotic therapy, and other considerations. If pulmonary status has unexpectedly improved when the patient is at or near the top of the waiting list, total survival may be improved by "inactivating the patient" until progression is again evident.

Stenotrophomonas maltophilia in cystic fibrosis: incidence and prevalence.

Stenotrophomonas maltophilia (SM) was recovered from 211 of 773 cystic fibrosis (CF) patients followed for at least one year, and seen between 1982 and 1994. Yearly prevalence (5.6% to 8.7%) and incidence rates (1.6% to 5.7%) showed no trends. SM persistence varied greatly and was unlike that of Pseudomonas aeruginosa. Fifty percent of SM-positive patients had only one positive culture and only 24 (11%) remained chronically infected. Although SM-positive patients were more likely to be hospitalized than SM-negative patients, for 55% of SM-positive patients, acquisition did not appear to follow hospitalization. Of 40 SM-positive patients who had a CF sibling, only 10 siblings were ever culture positive. When stratified by FEV1, the two-year survival for SM-positive with mild/moderate disease (98%) and severe disease (78%) was similar to that of our SM-negative patients. Five-year survival was only 40% for SM-positive patients with initially severe pulmonary status, compared with 72% for the SM-negative patients. Seventy percent of the original SM isolates were panresistant (susceptible to no more than one antimicrobial agent). Ten years later, panresistance was 84%. Despite our reassuring experience with SM, including lack of sibling concordance, the fact that the majority of our patients had no hospital exposure prior to acquisition, the high incidence of transient infection, and the seemingly unaffected two-year survival, there are insufficient data to definitively conclude that segregation of these patients would be beneficial. The increasing prevalence of multiply resistant gram-negative pathogens in CF patients suggests the need for continued caution with any panresistant pathogen.

Sodium space and intravascular volume: dietary sodium effects in cystic fibrosis and healthy adolescent subjects.

OBJECTIVE: To assess the physiologic response to salt depletion in subjects with cystic fibrosis (CF) and control male adolescents for sodium balance, sodium space, and stimulation of the renin-angiotensin-aldosterone axis. DESIGN: Seven subjects with CF and six controls received a salt-replete (150 or 290 mmol NaCl per day) diet and then a salt-deplete (10 mmol NaCl per day) diet while in a clinical research center. RESULTS: Space maintenance: CF subjects responded to salt depletion with a greater weight loss than did controls (1.9 vs 0.8 kg) and a decrease in 24Na+ space, whereas controls maintained 24Na+ space. Paired (Na-deplete/Na-replete) blood volumes decreased in subjects with CF, but not in controls. Renin-angiotensin-aldosterone axis stimulation: During salt repletion, subjects with CF had significantly higher aldosterone values than did controls in the afternoon, but not at 7:00 AM. During salt depletion, plasma renin activity and aldosterone increased significantly more in subjects with CF than in controls (renin, 35 vs 13 ng/mL/hour [9.7 vs 3.6 ng.L-1 s-1]; aldosterone: 181 vs 101 ng/dL [5021 vs 2802 pmol/L]). Furthermore, the angiotensin antagonist saralasin increased renin much more in subjects with CF (154 vs 36 ng/mL per hour [43 vs 10 ng.L-1 s-1]). Vasomotor functions: Mean arterial pressure was decreased in subjects with CF on both diets and decreased significantly more with low salt only in subjects with CF. During salt depletion, subjects with CF showed enhanced orthostatic tolerance (less heart rate increase with standing) compared with controls, thus obscuring their volume loss. The blood pressure response to an acute infusion of saralasin suggested that in salt-replete subjects with CF, but not in controls, angiotensin receptors were functional in maintaining vascular tone. During salt depletion, angiotensin was more important for maintenance of blood pressure in subjects with CF than in controls, because the saralasin-induced drop in blood pressure was 20%, ie, close to shock levels, in subjects with CF, and only 6% in controls. CONCLUSION: The data suggest that patients with CF are so successful in compensating for volume depletion by vigorous activation of the renin-angiotensin system that salt depletion/dehydration cannot be recognized easily by routine clinical measurements, eg, capillary refill, serum sodium levels, or tachycardia.

Pulmonary intralobar sequestration in a patient with cystic fibrosis.

We report a case in which pulmonary Intralobar Sequestration (ILS) was an incidental finding at autopsy in an adult with Cystic Fibrosis. Two aberrant arteries from the descending thoracic aorta supplied a bronchial cystic lesion in the right lower lobe. Termination of the segmental bronchus and scar formation proximal to the cyst suggested prior bronchial obliteration. The elastic configuration of the aberrant aortic-derived vessels of the sequestration contrasted sharply with massively hypertrophied, muscular, bronchial arteries which supplied the bronchiectatic upper lobe. Sections of inferior pulmonary ligament were studied in five additional patients with CF but without ILS. Small muscular arteries were consistently noted within the inferior pulmonary ligament. These histologic findings support the concept that the vascular portion of ILS is congenital, whereas the bronchocystic component, in some cases, may be acquired.

Nontuberculous mycobacteria in cystic fibrosis. An autopsy study.

We retrospectively studied lung and hilar lymph nodes at autopsy in 18 patients with cystic fibrosis (CF) who had antemortem sputum cultures positive for nontuberculous mycobacteria (NTM). Histologic features were compared with those of 18 patients with CF who had negative antemortem cultures. The most frequent species isolated was M. chelonae group (10 patients). Multiple cultures were positive for NTM in six patients. Three patients were clinically considered to be infected, and two received antimycobacteria drugs. Necrotizing pulmonary granulomas associated with granulomatous organizing pneumonia were found at autopsy in two patients, each of whom had multiple positive sputum cultures and clinical evidence of infection. In one of these, mycobacterial infection was considered to be an important factor in her terminal illness. Neither necrotizing granulomas nor granulomatous organizing pneumonia were seen in the lung tissue of patients whose antemortem cultures were negative for mycobacteria. There was no difference in the prevalence of other granuloma-like lesions between those with and those without positive sputum cultures. No mycobacteria-related granulomas occurred in hilar lymph nodes, although histoplasma granulomas involved hilar lymph nodes of three patients. We conclude that granulomatous mycobacterial lung disease is present in a minority of patients (two of six patients in this study) who have multiple positive cultures. Histologic evidence of infection was not found in patients who had only one of multiple sputum cultures positive for NTM.

Urolithiasis and cystic fibrosis.

PURPOSE: We determined whether cystic fibrosis patients are at increased risk for the development of urolithiasis. MATERIALS AND METHODS: Telephone interviews were conducted with 201 cystic fibrosis patients older than 15 years to identify those with a history of urolithiasis. Histories were confirmed by chart review, and only patients with urolithiasis documented by excretory urography, renal ultrasound or spontaneous passage of a stone were included. RESULTS: A total of 11 patients (5.5%) had documented urolithiasis, with 2 or more episodes in 7. Mean age at initial episode was 27.0 years (range 19 to 33). CONCLUSIONS: Cystic fibrosis patients may be at increased risk for urolithiasis compared to age-specific prevalence rates for stone disease in the general population.

Cross-sectional and longitudinal studies of naturally occurring antibodies to Pseudomonas aeruginosa in cystic fibrosis indicate absence of antibody-mediated protection and decline in opsonic quality after infection.

Most patients with cystic fibrosis (CF) develop chronic endobronchial infection with mucoid Pseudomonas aeruginosa. It has been suggested that opsonic antibodies to the mucoid exopolysaccharide of P. aeruginosa protect older CF patients (> 12 years of age) who have remained free of colonization by this organism. Serum antibodies from chronically infected CF patients had greater total complement-dependent opsonic activity than did those of older noncolonized patients (P < .02), but when bound antibody was equalized, opsonic quality was greater for the latter group (P < .03). In longitudinal studies, antibody titers to mucoid P. aeruginosa rose greatly after initial infection, but opsonic quality declined (P = .002). Twenty CF patients who passed age 12 free of P. aeruginosa colonization developed chronic P. aeruginosa lung infection at ages 14-35 years. Thus, naturally occurring antibodies do not protect CF patients from P. aeruginosa infection, and opsonic quality of serum antibodies deteriorates as infection becomes established.

3849+10 kb C-->T mutation and disease severity in cystic fibrosis.

50% of patients with cystic fibrosis (CF) are homozygous for the delta F508 mutation, but the remainder have at least one of many other less common mutations. The 3849 + 10 kb C-->T splice mutation seems to be associated with less severe disease. We report ten CF patients who are hemizygous for this mutation. Three male patients do not have azoospermia (sperm counts 12, 53, and 198 x 10(6)/mL). Another boy died before CF was diagnosed; his genital tract appeared normal at necropsy. All patients had clinically sufficient exocrine pancreatic function. Pulmonary disease was delayed in onset in most of these patients (range < 1 to 16; median 9 years), but then became severe in some, progressing to death (in two) and need for transplantation in one. Sweat chloride concentration was abnormal (80 mmol/L) in one patient but in others was in the intermediate range (45-65 mmol/L). There was substantial variation in pulmonary disease severity within sibships. These observations suggest some dissociation in genetically determined severity between different organs. There was some evidence among these patients of a tendency for disease of the genital tract to become progressively more severe. Perhaps sperm banking should be offered to male patients. We speculate that some normal CF transmembrane conductance regulator is made in patients with this splice abnormality.

Progression of pulmonary disease after disappearance of Pseudomonas in cystic fibrosis.

Once cystic fibrosis (CF) patients become chronically colonized, eradication of Pseudomonas aeruginosa (PA) is rare. We report five patients, each colonized for at least 6 yr, whose subsequent cultures did not reveal PA or any other gram-negative pathogen for at least 2 yr. Two patients harbored yeast, normal throat flora, and occasional colonies of Aspergillus fumigatus, but no PA, Haemophilus influenzae, or other gram-negative pathogens. In two patients, sputum cultures revealed Staphylococcus aureus. Sputum smear showed no gram-negative organisms in any patient. Antipseudomonal antibody titers in all patients decreased during the noncolonized period. However, titers increased in four other CF patients who had continued PA colonization. Despite disappearance of PA, four of five patients had clinical progression of lung disease with deterioration of FEV1. We conclude that (1) PA, even after it has chronically colonized the airways of CF patients, can occasionally disappear; and (2) lung disease can progress despite the disappearance of PA. Thus, the elimination of a milieu favorable to PA, such as might be anticipated with therapy directed at the basic defect, may not be sufficient to halt the pulmonary disease progression in CF.

Maternal child-rearing behavior in three groups: cystic fibrosis, insulin-dependent diabetes mellitus, and healthy children.

Compared child-rearing behaviors among mothers of children (ages 4-14) with cystic fibrosis (CF) (N = 26), insulin-dependent diabetes mellitus (IDDM) (N = 26), and mothers of physically healthy children (N = 26), on six domains, including involvement, limit setting, responsiveness, reasoning and guidance, free expression, and intimacy using the Iowa Parent Behavior Inventory. Maternal Reports of their child-rearing behavior were comparable across the three groups with one exception: Mothers of children with chronic illnesses (CF and IDDM) were significantly less likely to set limits than mothers of healthy children. The present findings are consistent with those of other studies that have identified few differences in child-rearing practices between mothers of children with chronic illnesses and mothers of healthy children. Future research should identify situation-specific parenting tasks unique to childhood chronic illness.