Clinical utility of circulating tumor DNA sequencing with a large panel: a National Center for Precision Medicine (PRISM) study.

BACKGROUND: Circulating tumor DNA (ctDNA) sequencing is a promising approach for tailoring therapy in patients with cancer. We report hereby the results from a prospective study where we investigated the impact of comprehensive molecular profiling of ctDNA in patients with advanced solid tumors. PATIENTS AND METHODS: Genomic analysis was performed using the FoundationOne Liquid CDx Assay [324 genes, tumor mutational burden (TMB), microsatellite instability status]. Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were classified by ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) tier leading to molecular-based treatment suggestions wherever it was possible. RESULTS: Between December 2020 and November 2021, 1772 patients with metastatic solid tumors underwent molecular profiling. Median time to assay results was 12 days. Results were contributive for 1658 patients (94%). At least one actionable target was detected in 1059 patients (64%) with a total of 1825 actionable alterations including alteration of the DNA damage repair response pathway (n = 336, 18%), high TMB (>16 mutations/Mb; n = 243, 13%), PIK3CA mutations (n = 150, 8%), ERBB family pathway alterations (n = 127, 7%), PTEN alterations (n = 95, 5%), FGFR alterations (n = 67, 4%) and MET activations (n = 13, 0.7%). The MTB recommended a matched therapy for 597 patients (56%) with a total of 819 therapeutic orientations: clinical trials (n = 639, 78%), off-label/compassionate use (n = 81, 10%), approved drug (n = 51, 6%), and early access program (n = 48, 6%). In total, 122 patients (21%) were treated. Among the assessable patients (n = 107), 4 (4%) had complete response, 35 (33%) had partial response, 27 (25%) had stable disease, and 41 (38%) a progressive disease as best response. The median progression-free survival and median overall survival were 4.7 months (95% confidence interval 2.7-6.7 months) and 8.3 months (95% confidence interval 4.7-11.9 months) respectively. CONCLUSIONS: ctDNA sequencing with a large panel is an efficient approach to match patients with advanced cancer with targeted therapies.

The management of cor pulmonale.

Pulmonary artery hypertension occurs when there is a sustained elevation of the mean pulmonary pressure above normal physiologic values. This may then lead to cor pulmonale or enlargement of the right ventricle due to any lung disease in the absence of left heart failure. When the ability of the right ventricle to compensate is overwhelmed, right-sided heart failure can occur. Pulmonary artery hypertension may be idiopathic (primary) or secondary to a variety of lung parenchymal diseases, airways disease, pulmonary circulatory disorders, systemic illnesses, or thoracic mechanical abnormalities. Treatment strategies for cor pulmonale include supplemental oxygen, assisted mechanical ventilation, digoxin, and diuretics. Pulmonary vasodilator compounds should be used with caution because they can compromise gas exchange in cor pulmonale from secondary pulmonary hypertension. Trials with digoxin and inotropic agents have been evaluated. Angiotensin-converting enzyme inhibitors have not shown significant utility, at least acutely. Anticoagulation may decrease mortality in some patients with pulmonary artery hypertension and cor pulmonale.

A scoring system for capnogram biofeedback: preliminary findings.

Labored breathing and irregularities in the breathing pattern may be assessed by capnography; and, an abnormal capnogram wave form may often be rectified with the help of capnogram biofeedback. Clinical experience suggests this may relieve dyspnea but to what degree, for how long and for what conditions have not been determined; the issue is complex and much remains to be discovered. The more that can be learned about the various capnogram irregularities, the more effectively such information will guide us in therapy and research. To this end a 15-category capnogram disordered breathing scale (Landis CDBS) was developed to provide a measure of disordered breathing. The CDBS score is the ratio of the total number of abnormal capnogram forms to the total number of capnogram configurations in the test sample, expressed as a percentage. The total score as well as an accounting of each abnormal scoring category was tabulated for each subject. In this retrospective and preliminary study, findings of a normal comparison group were compared with capnogram data for 3 clinical groups: asthma, anxiety/panic attacks, and patients with diverse stress-related somatic symptoms. Mean CDBS scores were: a low 14% for the Normal group compared with 64% for the Asthma group; 66% for the Anxiety patients; and 47% for the Somatic group. Each group was characterized by distinctive clusters of capnogram abnormalities. As there are methodological limitations to this small group study, the findings require validation. However, as an introduction to the scoring system and because of its potential clinical value we present this paper now.

Managed care accreditation: the process and early findings.

Health maintenance organizations (HMO)s are taking center stage in our nation's move toward healthcare reform. Issues such as quality, cost, and access to healthcare are critical to consumers; the managed care industry provides care at a significantly more affordable cost than does traditional fee-for-service medicine. Although national surveys show that HMO members are extremely satisfied with the level of service and care they receive, managed care organizations still strive to demonstrate their commitment to quality. As healthcare industry leaders and major customer groups attempt to establish measurable performance standards, the emergence of the National Committee for Quality Assurance (NCQA) has enhanced the ability of managed care organizations (MCOs) to demonstrate excellence by way of accreditation.

IL-1, IL-6, and PDGF mRNA expression in alveolar cells following stimulation with a tobacco-derived antigen.

To test the hypothesis that inflammatory cytokine production might be an early event in the development of the disease associated with smoking, we used alveolar cells from healthy nonsmokers stimulated with TGP as a model system. TGP, a phenol-rich glycoprotein which is present in tobacco leaves and cigarette smoke condensate, activates the immune system. It stimulates polyclonal B cell differentiation, induces primarily an IgE response, and activates human leukocytes to produce IL-1. Using in situ nucleic acid hybridization we show that the steady-state levels of IL-1 alpha, IL-1 beta, IL-6, platelet-derived growth factor (PDGF)-A, and PDGF-B mRNAs are consistently elevated in the alveolar cells of all donors following TGP stimulation. The kinetics of mRNA expression suggest that IL-1 alpha and IL-1 beta mRNAs are independently regulated in alveolar cells, while the regulation of PDGF-A and PDGF-B mRNA seems to be similar. The activated cells also synthesize elevated levels of IL-1 and IL-6. These findings lend support to the suggestion that some clinical consequences of smoking might be initiated and enhanced by the production of inflammatory cytokines. Moreover, IL-6 could also activate a polyclonal B cell response, which could lead to the synthesis of autoantibodies and thus cause immune-mediated tissue injury.

The pathogenesis, radiologic evaluation, and therapy of pleural effusions.

Radiology has played a pivotal role in the management of patients with pleural effusions. By confirming the presence of an effusion and providing information regarding the size and distribution of fluid, chest radiography greatly facilitates initial diagnostic thoracentesis. Identification of even small effusions is important because these commonly occur and may have clinical significance. The development of improved antibiotics and a wider range of interventional techniques has increased the reliance on the radiologic imaging of pleural disease in order to plan appropriate therapy. The newer imaging modalities of CT and sonography have proved to be particularly valuable in detecting small effusions and demonstrating single or multiple loculations. Additional features, such as the degree to which a pleural process has become organized and whether there is adjacent lung parenchymal disease, are well assessed on CT. Experience with MR has been limited, but preliminary data suggest that it may be a valuable addition and/or alternative to CT.

Na-dependent L-glutamate transport by eel intestinal BBMV: role of K+ and Cl-.

L-[3H]glutamate uptake into eel (Anguilla anguilla) intestinal brush-border membrane vesicles (BBMV) was a sigmoidal function of extravesicular Na, suggesting that two or more cations accompanied the amino acid during transport. L-[3H]glutamate influx illustrated the following kinetic constants: apparent membrane binding affinity (Kapp) = 0.80 +/- 0.12 mM; influx velocity (Jmax) = 2.61 +/- 0.31 nmol.mg protein-1.min-1; and permeability coefficient (P) = 0.65 +/- 0.10 microliters.mg protein-1. min-1. Results from the imposition of diffusion potentials across vesicle membranes using K-valinomycin or H-carbonyl-cyanide p-chloromethoxyphenylhydrazone suggested that Na-dependent L-glutamate transport was sensitive to transmembrane electrical potential difference. Extravesicular aspartate was a competitive inhibitor of L-[3H]glutamate influx [inhibitory constant (Ki) = 0.28 +/- 0.04 mM]. Intravesicular K and extravesicular Cl ions enhanced maximal amino acid influx and transient L-glutamate accumulation against a concentration gradient (overshoot). Intravesicular K reduced the Kapp of the membrane to L-glutamate, whereas extravesicular Cl increased L-glutamate Jmax. A model for L-[3H]glutamate transport is suggested involving the cotransport of at least two Na and one L-glutamate that is activated by one intravesicular K ion and at least two extravesicular Cl ions.

Acute pulmonary edema associated with the use of oral ritodrine for premature labor.

We describe a patient who developed acute pulmonary edema while taking oral ritodrine for the treatment of premature labor and recovered after its discontinuation. The mechanism of development of pulmonary edema associated with beta-sympathomimetic agents is still not fully understood. Patients taking oral ritodrine should be observed for cardiopulmonary signs and symptoms.

Pleural effusions: pathogenesis, radiologic evaluation, and therapy.

The imaging of pleural effusions by plain radiography, sonography, computed tomography (CT), and magnetic resonance imaging (MRI) has greatly facilitated the planning of both initial diagnostic thoracentesis and subsequent therapeutic management. The normal anatomy and physiology of the pleura, the pathogenesis of effusions, and the clinical criteria for classifying effusions are briefly summarized. The usefulness of each imaging modality is then discussed, particularly with regard to the problems of detecting small effusions, identifying loculation of fluid, distinguishing pleural from intraparenchymal disease, and assessing the extent to which a pleural process has become organized.

QA in a health maintenance organization IPA model.

The PRO is working collaboratively with the American Medical Peer Review Association (AMPRA), the Group Health Association of America (GHAA), the American Medical Care and Review Association (AMCRA) and the California Association of HMOs, Inc. to develop meaningful and acceptable methodology for future review. It has become clear that both the PRO and the HMO must modify systems in order to accomplish stated objectives in the unique IPA setting. Internally, the HMO must rethink management information systems in order to provide data in a timely fashion. The PRO, as well, must strive to understand how an IPA model differs from fee-for-service Medicare review and be prepared to modify exiting systems so defined by their contract with HCFA. Managed care in any model imposes the same responsibility for quality as other health care delivery systems. Only by cooperation and support of the quality process in concert with providers and review organizations can the IPA model measure whether the quality of its services meet professionally recognized standards of health care and whether appropriate health care services have been provided in appropriate settings.