Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial.

BACKGROUND AND PURPOSE: Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO-TTR study in patients with hATTR polyneuropathy. Here, the long-term efficacy and safety of inotersen are assessed in an ongoing open-label extension (OLE) study. METHODS: Patients who completed NEURO-TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score and the Short-Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed. RESULTS: Overall, 97% (135/139) of patients who completed NEURO-TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO-TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL-DN and SF-36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure. CONCLUSION: Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long-term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed.

Tandem cycles of high-dose melphalan and autologous stem cell transplantation increases the response rate in AL amyloidosis.

Clinical outcomes of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation (HDM/SCT) are tightly linked to the achievement of a hematologic complete response (HCR). We conducted a prospective trial to determine whether a second cycle of HDM/SCT could induce HCR in patients in whom the plasma cell dyscrasia persisted following initial treatment with HDM/SCT. Sixty-two patients were enrolled. Nine patients (15%) were removed from the protocol. Of the 53 patients continuing in this study, four died within 100 days of treatment (8%), and 27 (55%) achieved an HCR at 6 months after the first cycle of HDM/SCT. Of the 22 patients who did not achieve an HCR after initial treatment, 17 received a second HDM/SCT, 1 died within 100 days of treatment (6%), while 5 (31%) achieved an HCR. Thus, the HCR rate was 67% (32/48) for surviving patients on study, 60% (32/53) for all patients who received initial cycle of HDM/SCT, and 56% (35/62) by intention-to-treat. The median survival for all patients enrolled on the trial has not yet been reached. Thus, tandem cycles of HDM/SCT can increase the proportion of patients who achieve an HCR.

Retinoic acid-induced inhibition of type I collagen gene expression by human lung fibroblasts.

We examined alpha 1(I) collagen gene expression in all-trans retinoic acid (RA)-treated human lung fibroblast cultures. RA (10(-5)M) decreased steady-state levels for alpha 1(I) collagen mRNA by at least 75% after 24 h. The inhibition was evident within 8 h after addition of RA, was dose dependent and reversible. Treatment with 9-cis-retinoic acid did not affect alpha 1(I) collagen mRNA levels. RA also inhibited the increases in alpha 1(I) mRNA stimulated by transforming growth factor-beta (TGF-beta). The RA-mediated decrease in alpha 1(I) collagen mRNA was blocked by cycloheximide treatment, suggesting that synthesis of a protein intermediate is required for the inhibition. The RA-induced decrease in alpha 1(I) collagen mRNA levels was not mediated by increases in prostaglandin E2 production. RA decreased alpha 1(I) gene transcription as determined by nuclear run-off assays but did not significantly alter the rate of degradation of the alpha 1(I) transcript as determined by actinomycin D treatment. Studies employing cells stably transfected with constructs containing portions of the alpha 1(I) collagen promoter indicate that the DNA sequences which mediate the inhibitory effect are located within 900 bases from the transcription start site.

Tracheobronchial amyloidosis. The Boston University experience from 1984 to 1999.

Tracheobronchial amyloidosis (TBA), an idiopathic disorder characterized by deposition of fibrillar proteins in the tracheobronchial tree, occurred in 10 patients referred to the Amyloid Program at Boston University over the past 15 years. Fewer than 100 cases of TBA have been described; only 1 series encompassed more than 3 patients. We analyzed our experience with biopsy-proven TBA to define better its natural history. Follow-up averaged approximately 8 years and was obtained in all cases, making this outcome reporting the largest and most complete to date. Three of these patients were prospectively studied for up to 24 months to examine the utility of bronchoscopy, computerized tomography (CT) imaging, and pulmonary function tests (PFTs) in monitoring disease progression. No patient with TBA developed signs or symptoms of systemic amyloidosis during the period reviewed. Conversely, tracheobronchial disease was not diagnosed in 685 patients with primary systemic (AL) amyloidosis during the 15-year study period at Boston University. Bronchoscopy proved most useful in establishing the diagnosis by biopsy. Narrowing of major airways limited its inspection of the tracheobronchial tree, however. In contrast, CT imaging provided quantitative assessment of airway narrowing and mural thickening--2 major consequences of amyloid infiltration. These CT features, in the presence of mural calcifications sparing the posterior tracheal membrane, have been reported in few disorders other than TBA. The ability of CT to map airway involvement and identify extraluminal manifestations of TBA made it the study of choice for establishing disease extent. Three patterns of disease were evident by CT imaging and bronchoscopic examination: proximal, mid, and distal airways involvement. Those with severe proximal disease had significantly decreased air flows, air trapping, and fixed upper airway obstruction on PFTs. Patients with distal disease had normal airflows. PFTs could not clearly distinguish proximal from severe mid airways disease. Thirty percent of patients died within 7-12 years after diagnosis, all having proximal or severe mid airways disease. Repeated rigid bronchoscopic debridement and laser treatments did not prevent progressive airways narrowing in patients dying from TBA. Most patients with mid airways involvement, and all distal airway cases, had either stagnant disease or slowly increasing amyloid deposits when followed for up to 14 years. In a small subset of patients followed prospectively, serial PFTs were most sensitive to disease progression. CT-derived measures of airway lumen diameter and wall thickness did not change significantly despite marked improvements in airflow after rigid bronchoscopy. Our experience suggests that serial PFTs and CT imaging together offer the best assessment of airway involvement and disease progression in patients with TBA. In the future, radiation therapy may provide more definitive treatment of TBA than debulking procedure have to date.

Gunshot wounds of the esophagus.

During a 4 year period between 1970 and 1974 there were eleven esophageal gunshot wounds representing 52 per cent of the total esophageal perforations. The increased incidence of esophageal gunshot wounds reflects the higher rate of civilian gunshot injuries. There were six perforations in the cervical portion of the esophagus and five in the thoracic portion, with three located above the aortic arch, one in the midesophagus, and one in the lower third. Symptoms are less diagnostic than in esophageal perforations from other causes because the gunshot wound tends to mask the complaints related to mediastinitis. The signs are similar. In 9 patients free air was present in the neck or mediastinum and in 10 patients the diagnosis was confirmed by barium swallow. Of the 2 patients without free air, one had a lateral thoracic wound and esophageal injury was not suspected; the diagnosis was made by drainage of oral feeding through a thoracostomy and confirmed by barium swallow. In the other patient the perforation was found during surgery for hemothorax. Primary repair with drainage was done in the group with cervical injuries. All survived with no serious complications. In the group with thoracic injuries, fistulas developed in 2 of 3 patients who had primary repair with drainage. Two patients with extensive injuries of the esophagus treated by defunctionalization did well but required a second procedure. It is concluded that gunshot wounds of the cervical esophagus, if treated promptly by suture and drainage, will do well. Thoracic injuries represent a more difficult problem and it is suggested that defunctionalization of the esophagus is the safest procedure, particularly if damage is extensive.

High-dose intravenous melphalan and autologous stem cell transplantation as initial therapy or following two cycles of oral chemotherapy for the treatment of AL amyloidosis: results of a prospective randomized trial.

SUMMARY: A prospective randomized trial was conducted to study the timing of high-dose intravenous melphalan and autologous stem cell transplantation (HDM/SCT) in AL amyloidosis. In all, 100 newly diagnosed patients were randomized to receive HDM/SCT, either as initial therapy (Arm-1) or following two cycles of oral melphalan and prednisone (Arm-2). The objectives of the trial were to compare survival and hematologic and clinical responses. With a median follow-up of 45 months (range 24-70), the overall survival was not significantly different between the two treatment arms (P=0.39). The hematologic response and organ system improvements after treatment did not differ between the two groups. Fewer patients received HDM/SCT in Arm-2 because of disease progression during the oral chemotherapy phase of the study, rendering them ineligible for subsequent high-dose therapy. This affected patients with cardiac involvement particularly, and led to a trend for an early survival disadvantage in Arm-2. Hence, newly diagnosed patients with AL amyloidosis eligible for HDM/SCT did not benefit from initial treatment with oral melphalan and prednisone, and there was a survival disadvantage for patients with cardiac involvement if HDM/SCT was delayed by initial oral chemotherapy.

The role of adrenergic stimulation in the pathogenesis of pulmonary insufficiency.

Recent studies have shown that epinephrine (E), norepinephrine (NE), and isoproterenol (I) caus'e substantial pulmonary shunting. This study was undertaken to determine the role of alpha (pulmonary vasconconstriction) and beta (pulmonary vasodilatation) adrenergic stimulation in the pathogenesis of pulmonary insufficiency. Forty-three mechanically ventilated, anesthetized dogs received infusions of E, alpha and beta stimulant; NE, a relatively pure alpha stimulant; I, a relatively pure beta stimulant; and dextran (D), a drug with no known adrenergic activity. The cardiac output and shunt measurements were determined simultaneously in the control period and four times during a 1 hour infusion. The quadratic equation of best fit was determined for each group for the relationship between the cardiac output and the shunt over a wide range of cardiac outputs, and statistical comparisons were made between all groups of the shunt at the same cardiac output. In all groups an increase in cardiac output was associated with an increase in the shunt, but the magnitude of the increase in the shunt differed significantly with each drug over the entire range, being smallest with D and becoming progressively larger with I, E, and NE, respectively. It is concluded that an increase in the pulmonary blood flow causes an increase in the pulmonary shunt, but that the magnitude of the increase is dependent on the specific pulmonary microcirculatory effects of each drug.

Hypoxia inhibits amino acid uptake in human lung fibroblasts.

Hypoxia and amino acid deprivation downregulate expression of extracellular matrix genes in lung fibroblasts. We examined the effect of hypoxia on amino acid uptake and protein formation in human lung fibroblasts. Low O(2) tension (0% O(2)) suppressed incorporation of [(3)H]proline into type I collagen without affecting [(35)S]methionine labeling of other proteins. Initial decreases in intracellular [(3)H]proline incorporation occurred after 2 h of exposure to 0% O(2), with maximal suppression of intracellular [(3)H]proline levels at 6 h of treatment. Hypoxia significantly inhibited the uptake of radiolabeled proline, 2-aminoisobutyric acid (AIB), and 2-(methylamino)isobutyric acid (methyl-AIB) while inducing minor decreases in leucine transport. Neither cycloheximide nor indomethacin abrogated hypoxia-related suppression of methyl-AIB uptake. Efflux studies demonstrated that hypoxia inhibited methyl-AIB transport in a bidirectional fashion. The downregulation of amino acid transport was not due to a toxic effect; function recovered on return to standard O(2) conditions. Kinetic analysis of AIB transport revealed a 10-fold increase in K(m) accompanied by a small increase in maximal transport velocity among cells exposed to 0% O(2). These data indicate that low O(2) tension regulates the system A transporter by decreasing transporter substrate affinity.

Cold-induced bronchoconstriction: role of cutaneous reflexes vs. direct airway effects.

To determine the relative contributions of direct airway vs. reflex cutaneous thermal receptor stimulation in cold-induced bronchoconstriction, we isolated these two aspects of cold exposure in 10 asthmatics and 13 normal subjects. Ice packs were applied to the skin of the face, chest, thigh, and upper arm in random sequence while serially measuring specific conductance. In this fashion a limited mapping of skin-mediated bronchoconstriction was established. Warm packs were applied to the same areas of control for any potential nonspecific stimulatory effects. Cooling the skin induced bronchoconstriction to a similar degree in both groups; this effect was very small, did not induce symptoms, and was only seen with stimulation of the face. At another time, the subjects performed isocapnic hyperventilation of frigid air to ascertain their response to direct airway cooling. A moderate but significant correlation existed between skin and airway sensitivity; however, the magnitude of the two responses differed markedly. Breathing cold air at rest had no effect on lung function; however, elevating ventilation promptly produced bronchial narrowing. Hence, in a cold environment, the most potent stimulus for the development of airway obstruction in asthmatics derives from a direct airway effect.

Nonocclusive mesenteric vascular insufficiency.

A 74-year-old man had probable nonocclusive intestinal ischemia after myocardial infarction. Angiography and careful monitoring of the patient's hemodynamic status allowed diagnosis and appropriate supportive treatment leading to recovery.

Simple, rapid method for insertion of a Swan-Ganz catheter using an existing central venous or Swan-Ganz catheter.

A method is described for simple, rapid Swan-Ganz catheter insertion. In addition, a new technique for replacement of Swan-Ganz catheters without the need for additional venipuncture is presented.

Momitoring the patient in shock: what, when, and how.

In critically ill patients there is frequently more than one problem, which may not be obvious, contributing to the shock state. The history, physical exam, and monitoring devices may not be reliable individually, but must be considered together and interpreted in the light of the pathophysiologic mechanisms involved. A plan for monitoring and treating critically ill patients is outlined. The advantages and limitations of various monitoring techniques are discussed.

Use of vasoactive drugs in the treatment of shock.

The effective use of vasoactive drugs in shock requires an understanding of the pathophysiologic mechanisms involved in the various types and stages of shock and knowledge of the specific pharmacologic effects of each drug in the abnormal state. Vasoactive drugs should be used after the primary and secondary causes of shock have been corrected. Specific vasoactive drugs should be selected on the basis of measured hemodynamic abnormalities.

Safety and efficacy of high-dose melphalan and auto-SCT in patients with AL amyloidosis and cardiac involvement.

In Ig light chain (AL) amyloidosis, cardiac involvement is associated with worse prognosis and increased treatment-related complications. In this retrospective cohort study, we assessed survival, hematologic and cardiac responses to high-dose melphalan and auto-SCT (HDM/SCT) in patients with AL amyloidosis and cardiac involvement, stratified by cardiac biomarkers brain natriuretic peptide and Troponin I, analogous to the Mayo cardiac staging. Forty-seven patients underwent HDM/SCT based upon functional measures; six patients had modified cardiac stage I disease, seventeen had modified cardiac stage II disease and twenty-four had modified cardiac stage III disease. Treatment-related mortality was 4% for all patients and 8% for patients with stage III disease. Three-year survival was 88% and EFS was 47%; these did not differ by stage. By intention-to-treat analysis, 27% of patients achieved a hematologic complete response and 32% a very good partial response, of whom 70 and 45%, respectively, have not required additional therapy at 36 months. Cardiac response was achieved in 53% of patients. We conclude that with appropriate patient selection and a risk-adapted treatment approach, HDM/SCT is safe and effective in patients with AL amyloidosis and cardiac involvement.

Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials.

Protein stabilization and oligonucleotide therapies are being tested in transthyretin amyloid polyneuropathy (TTR FAP) trials. From retrospective analysis of 97 untreated TTR FAP patients, we test the adequacy of Neuropathy Impairment Score+7 tests (NIS+7) and modifications to comprehensively score impairments for use in such therapeutic trials. Our data confirms that TTR FAP usually is a sensorimotor polyneuropathy with autonomic features which usually is symmetric, length dependent, lower limb predominant and progressive. NIS+7 adequately assesses weakness and muscle stretch reflexes without ceiling effects but not sensation loss, autonomic dysfunction or nerve conduction abnormalities. Three modifications of NIS+7 are suggested: 1) use of Smart Somatotopic Quantitative Sensation Testing (S ST QSTing); 2) choice of new autonomic assessments, e.g., sudomotor testing of distributed anatomical sites; and 3) use of only compound muscle action potential amplitudes (of ulnar, peroneal and tibial nerves) and sensory nerve action potentials of ulnar and sural nerve - than the previously recommended attributes suggested for the sensitive detection of diabetic sensorimotor polyneuropathy. These modifications of NIS+7 if used in therapeutic trials should improve characterization and quantification of sensation and autonomic impairment in TTR FAP and provide better nerve conduction tests.