High-Temporal-Resolution Kinetic Modeling of Lung Tumors with Dual-Blood Input Function Using Total-Body Dynamic PET.

The lungs are supplied by both the pulmonary arteries carrying deoxygenated blood originating from the right ventricle and the bronchial arteries carrying oxygenated blood downstream from the left ventricle. However, this effect of dual blood supply has never been investigated using PET, partially because the temporal resolution of conventional dynamic PET scans is limited. The advent of PET scanners with a long axial field of view, such as the uEXPLORER total-body PET/CT system, permits dynamic imaging with high temporal resolution (HTR). In this work, we modeled the dual-blood input function (DBIF) and studied its impact on the kinetic quantification of normal lung tissue and lung tumors using HTR dynamic PET imaging. Methods: Thirteen healthy subjects and 6 cancer subjects with lung tumors underwent a dynamic 18F-FDG scan with the uEXPLORER for 1 h. Data were reconstructed into dynamic frames of 1 s in the early phase. Regional time-activity curves of lung tissue and tumors were analyzed using a 2-tissue compartmental model with 3 different input functions: the right ventricle input function, left ventricle input function, and proposed DBIF, all with time delay and dispersion corrections. These models were compared for time-activity curve fitting quality using the corrected Akaike information criterion and for differentiating lung tumors from lung tissue using the Mann-Whitney U test. Voxelwise multiparametric images by the DBIF model were further generated to verify the regional kinetic analysis. Results: The effect of dual blood supply was pronounced in the high-temporal-resolution time-activity curves of lung tumors. The DBIF model achieved better time-activity curve fitting than the other 2 single-input models according to the corrected Akaike information criterion. The estimated fraction of left ventricle input was low in normal lung tissue of healthy subjects but much higher in lung tumors (∼0.04 vs. ∼0.3, P < 0.0003). The DBIF model also showed better robustness in the difference in 18F-FDG net influx rate [Formula: see text] and delivery rate [Formula: see text] between lung tumors and normal lung tissue. Multiparametric imaging with the DBIF model further confirmed the differences in tracer kinetics between normal lung tissue and lung tumors. Conclusion: The effect of dual blood supply in the lungs was demonstrated using HTR dynamic imaging and compartmental modeling with the proposed DBIF model. The effect was small in lung tissue but nonnegligible in lung tumors. HTR dynamic imaging with total-body PET can offer a sensitive tool for investigating lung diseases.

Emerging precision neoadjuvant systemic therapy for patients with resectable non-small cell lung cancer: current status and perspectives.

Over the past decade, targeted therapy for oncogene-driven NSCLC and immune checkpoint inhibitors for non-oncogene-driven NSCLC, respectively, have greatly improved the survival and quality of life for patients with unresectable NSCLC. Increasingly, these biomarker-guided systemic therapies given before or after surgery have been used in patients with early-stage NSCLC. In March 2022, the US FDA granted the approval of neoadjuvant nivolumab and chemotherapy for patients with stage IB-IIIA NSCLC. Several phase II/III trials are evaluating the clinical efficacy of various neoadjuvant immune checkpoint inhibitor combinations for non-oncogene-driven NSCLC and neoadjuvant molecular targeted therapies for oncogene-driven NSCLC, respectively. However, clinical application of precision neoadjuvant treatment requires a paradigm shift in the biomarker testing and multidisciplinary collaboration at the diagnosis of early-stage NSCLC. In this comprehensive review, we summarize the current diagnosis and treatment landscape, recent advances, new challenges in biomarker testing and endpoint selections, practical considerations for a timely multidisciplinary collaboration at diagnosis, and perspectives in emerging neoadjuvant precision systemic therapy for patients with resectable, early-stage NSCLC. These biomarker-guided neoadjuvant therapies hold the promise to improve surgical and pathological outcomes, reduce systemic recurrences, guide postoperative therapy, and improve cure rates in patients with resectable NSCLC.

Stability of Whole Blood Electrolyte Specimens at Room Temperature vs. Slushed Ice Conditions.

BACKGROUND: Data on the stability of whole blood electrolytes is limited to small sample sizes. We sought to determine the stability of whole blood electrolytes under room temperature and slushed iced conditions in human patients at a major hospital center. METHODS: Whole blood samples were obtained from 203 patients hospitalized for various pathophysiological conditions. Electrolyte concentrations of sodium, potassium [K+], ionized calcium, and chloride were measured at 5 different timepoints spanning 3 h. Samples were stored at room temperature (22-24 °C) or under slushed ice conditions (0.1-0.2 °C) before analysis. RESULTS: Under both conditions, sodium, ionized calcium, and chloride did not show a measurable change up to 109 min compared to baseline; however, the mean increase in [K+] over 138 min of storage in slushed ice was 0.0032 (0.0021 [5th percentile] to 0.0047 [95th percentile]) mmol/L/min (adjusted R2 = 0.62, P < 0.001). Five percent of the specimens demonstrated a ≥0.3 mmol/L change in [K+] from baseline after 67 min of storage in slushed ice. In contrast, 1% of the specimens stored at room temperature showed the same change at the same timepoint. CONCLUSIONS: Whole blood sodium, [K+], ionized calcium, and chloride concentrations remain stable for at least 109 min at room temperature. However, whole blood specimens stored in slushed ice for not more than 67 min exhibit a 5% probability that the [K+] concentration will increase by at least 0.3 mmol/L compared to baseline. The other analytes do not destabilize for up to 178 min of slushed ice storage.

Stability of Whole Blood Lactate Specimens at Room Temperature Versus Slushed Ice Conditions.

BACKGROUND: There are limited data on lactate stability in whole blood. The purpose of this study was to determine whole blood lactate stability at room temperature and in slushed ice conditions. METHODS: An equal number of arterial and venous samples were obtained from 202 subjects hospitalized for various pathophysiological conditions. Whole blood lactate concentration was measured over 5 different times spanning 80-90 min in a blood gas lab at a major hospital center. Samples were stored at room temperature (22-24°C) or in slushed ice conditions (0.1-0.2°C) before analysis. RESULTS: The mean increase in lactate concentration was 0.001 mmol/L/min in samples on slushed ice over 90 min. However, at room temperature conditions, the mean increase in lactate concentration was 0.008 mmol/L/min regardless of whether the sample was arterial or venous. An increase in whole blood lactate concentration of ≥ 0.4 mmol/L occured after 45 min at room temperature, with 5% of all whole blood specimens demonstrating a meaningful change at ≤ 20 min. The ≥ 0.4 mmol/L change in whole blood lactate is considered significant based on the College of American Pathologists instrument peer-group standards. CONCLUSIONS: Considering that a change in whole blood lactate concentration of ≥ 0.4 mmol/L is unacceptable instrument peer-group variation as defined by the College of American Pathologists, ice is no longer needed to stabilize whole blood lactate specimens when the draw time to analyze time is < 45 min. Samples remain stable even at 90 min when left on ice.

Interstitial Lung Disease Associated With Crizotinib in Patients With Advanced Non-Small Cell Lung Cancer: Independent Review of Four PROFILE Trials.

INTRODUCTION: Interstitial lung disease (ILD) is a rare, but potentially serious, side effect associated with crizotinib, a tyrosine kinase inhibitor for anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer. Our objective was to determine the incidence and nature of ILD associated with crizotinib in 4 PROFILE trials (ClinicalTrials.gov identifiers, NCT00585195, NCT00932451, NCT00932893, and NCT01154140). MATERIALS AND METHODS: Grade ≥ 3 respiratory adverse events (AEs) and serious AEs (SAEs) and any grade AEs/SAEs reported as pneumonitis, ILD, or radiation pneumonitis in trials PROFILE 1001, PROFILE 1005, PROFILE 1007, and PROFILE 1014 were evaluated by an expert independent review committee that included a pulmonologist, medical oncologist, and radiologist. Events were designated as disease progression, de novo ILD possibly or probably related to crizotinib, exacerbation or recurrence of pre-existing ILD, concurrent illness, other toxicity not thought to be related to ILD, or inconclusive. RESULTS: The independent review committee evaluated 446 events (in 368 of 1669 patients who had received crizotinib therapy). They classified these events as follows: progressive disease, 77; de novo ILD, 20; pre-existing ILD, 3; concurrent illness, 9; other toxicities, 310; and inconclusive, 27. The incidence of de novo ILD was 1.2% overall, 1.3% in whites, and 1.2% overall in Asians, but greater at 3.7% in Japanese patients. The median onset of ILD from the initiation of crizotinib therapy was 23 days (range, 3-763 days). The mortality rate due to ILD was 50%. Survival was improved if crizotinib was discontinued on presentation of ILD (9 of 14 patients) compared with discontinued later or continued (1 of 6 patients). CONCLUSION: ILD associated with crizotinib, although rare, can occur at any time and requires close monitoring.

Acute Fibrinous and Organizing Pneumonia Associated With Allogenic Hematopoietic Stem Cell Transplant Successfully Treated With Corticosteroids: A Two-Patient Case Series.

Acute fibrinous and organizing pneumonia (AFOP) is an extremely rare, relatively new, and distinct histological pattern of acute lung injury characterized predominately by the presence of intra-alveolar fibrin and associated organizing pneumonia. AFOP may be idiopathic or associated with a wide spectrum of clinical conditions. It has a variable clinical presentation from mild respiratory symptoms to that similar to the acute respiratory distress syndrome. Currently there is no consensus on treatment, and corticosteroids previously were of unclear benefit. To date, there are less than 40 cases of AFOP reported in the literature and only one has been linked to hematopoietic stem cell transplantation. Here we report the first case series of 2 patients who developed AFOP following allogenic stem cell transplant that were successfully treated with high-dose corticosteroids.

Safety and Clinical Utility of Flexible Bronchoscopic Cryoextraction in Patients With Non-neoplasm Tracheobronchial Obstruction: A Retrospective Chart Review.

BACKGROUND: Airway obstruction from blood clots, airway secretions, and foreign bodies is a potentially life-threatening condition. Optimal management of this problem, whether by rigid or flexible bronchoscopy, has not been well studied. We report our single-center experience on the safety and clinical utility of cryoprobe extraction for this indication. METHODS: We performed a retrospective chart review from January 2006 to November 2014 of all subjects aged 18 and older who underwent flexible bronchoscopic cryoprobe extraction. Subjects with obstruction due to benign or malignant neoplasm or airway stenosis were excluded. RESULTS: A total of 38 cryotherapy sessions performed on 30 subjects were identified for inclusion. Cryoprobe extraction was successful in reestablishing airway patency in 32/38 (84%) sessions overall and in 24/26 (92%) for blood clots, 4/6 (67%) for mucous plugging, 2/4 (50%) for foreign bodies, and 2/2 (100%) for plastic bronchitis. Twenty-one of 31 (68%) sessions resulted in improvement in oxygenation or ventilation. There was 1 complication related to sedation. CONCLUSIONS: We conclude that flexible bronchoscopic cryoprobe extraction of blood clots, mucous secretions, plastic bronchitis, and foreign bodies is a safe and effective option. It can be safely performed at the bedside and in many cases eliminates the need for rigid bronchoscopy.

A fresh look at paralytics in the critically ill: real promise and real concern.

Neuromuscular blocking agents (NMBAs), or "paralytics," often are deployed in the sickest patients in the intensive care unit (ICU) when usual care fails. Despite the publication of guidelines on the use of NMBAs in the ICU in 2002, clinicians have needed more direction to determine which patients would benefit from NMBAs and which patients would be harmed. Recently, new evidence has shown that paralytics hold more promise when used in carefully selected lung injury patients for brief periods of time. When used in early acute respiratory distress syndrome (ARDS), NMBAs assist to establish a lung protective strategy, which leads to improved oxygenation, decreased pulmonary and systemic inflammation, and potentially improved mortality. It also is increasingly recognized that NMBAs can cause harm, particularly critical illness polyneuromyopathy (CIPM), when used for prolonged periods or in septic shock. In this review, we address several practical considerations for clinicians who use NMBAs in their practice. Ultimately, we conclude that NMBAs should be considered a lung protective adjuvant in early ARDS and that clinicians should consider using an alternative NMBA to the aminosteroids in septic shock with less severe lung injury pending further studies.

Nitrofurantoin compares favorably to recommended agents as empirical treatment of uncomplicated urinary tract infections in a decision and cost analysis.

OBJECTIVE: To analyze the costs of nitrofurantoin use compared to those of other antibiotics recommended for treatment of uncomplicated urinary tract infection (UTI). PATIENTS AND METHODS: We used a decision analysis model to perform cost-minimization and sensitivity analyses to determine the level of trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolone resistance that would favor the use of nitrofurantoin as a first-line empirical treatment of uncomplicated UTIs. The model used a program perspective to evaluate costs. RESULTS: Nitrofurantoin was cost-minimizing when the prevalence of fluoroquinolone resistance exceeded 12% among uropathogens or the prevalence of TMP-SMX resistance exceeded 17%. On 2-way sensitivity analysis, variables that had a significant impact on our cost-minimization threshold included cost of antibiotics and probability of clinical cure with antibiotics. CONCLUSION: From a payer perspective, nitrofurantoin appears to be a reasonable alternative to TMP-SMX and fluoroquinolones for empirical treatment of uncomplicated UTIs, especially given the current prevalence of antibiotic resistance among community uropathogens. On the basis of efficacy, cost, and low impact on promoting antimicrobial resistance, clinicians should consider nitrofurantoin as a reasonable alternative to TMP-SMX and fluoroquinolones for first-line therapy for uncomplicated UTIs.

Bench-to-bedside review: rare and common viral infections in the intensive care unit--linking pathophysiology to clinical presentation.

Viral infections are common causes of respiratory tract disease in the outpatient setting but much less common in the intensive care unit. However, a finite number of viral agents cause respiratory tract disease in the intensive care unit. Some viruses, such as influenza, respiratory syncytial virus (RSV), cytomegalovirus (CMV), and varicella-zoster virus (VZV), are relatively common. Others, such as adenovirus, severe acute respiratory syndrome (SARS)-coronavirus, Hantavirus, and the viral hemorrhagic fevers (VHFs), are rare but have an immense public health impact. Recognizing these viral etiologies becomes paramount in treatment, infection control, and public health measures. Therefore, a basic understanding of the pathogenesis of viral entry, replication, and host response is important for clinical diagnosis and initiating therapeutic options. This review discusses the basic pathophysiology leading to clinical presentations in a few common and rare, but important, viruses found in the intensive care unit: influenza, RSV, SARS, VZV, adenovirus, CMV, VHF, and Hantavirus.

Acute febrile respiratory illness in the ICU: reducing disease transmission.

Acute febrile respiratory illness (FRI) leading to respiratory failure is a common reason for admission to the ICU. Viral pneumonia constitutes a portion of these cases, and often the viral etiology goes undiagnosed. Emerging viral infectious diseases such as severe acute respiratory syndrome and avian influenza present with acute FRIs progressing to respiratory failure and ARDS. Therefore, early recognition of a viral cause of acute FRI leading to ARDS becomes important for protection of health-care workers (HCWs), lessening spread to other patients, and notification of public health officials. These patients often have longer courses of viral shedding and undergo higher-risk procedures that may potentially generate aerosols, such as intubation, bronchoscopy, bag-valve mask ventilation, noninvasive positive pressure ventilation, and medication nebulization, further illustrating the importance of early detection and isolation. A small number of viral agents lead to acute FRI, respiratory failure, and ARDS: seasonal influenza, avian influenza, coronavirus associated with severe ARDS, respiratory syncytial virus, adenovirus, varicella, human metapneumovirus, and hantavirus. A systematic approach to early isolation, testing for these agents, and public health involvement becomes important in dealing with acute FRI. Ultimately, this approach will lead to improved HCW protection, reduction of transmission to other patients, and prevention of transmission in the community.