Ultra-fast deep-learned CNS tumour classification during surgery.

Central nervous system tumours represent one of the most lethal cancer types, particularly among children1. Primary treatment includes neurosurgical resection of the tumour, in which a delicate balance must be struck between maximizing the extent of resection and minimizing risk of neurological damage and comorbidity2,3. However, surgeons have limited knowledge of the precise tumour type prior to surgery. Current standard practice relies on preoperative imaging and intraoperative histological analysis, but these are not always conclusive and occasionally wrong. Using rapid nanopore sequencing, a sparse methylation profile can be obtained during surgery4. Here we developed Sturgeon, a patient-agnostic transfer-learned neural network, to enable molecular subclassification of central nervous system tumours based on such sparse profiles. Sturgeon delivered an accurate diagnosis within 40 minutes after starting sequencing in 45 out of 50 retrospectively sequenced samples (abstaining from diagnosis of the other 5 samples). Furthermore, we demonstrated its applicability in real time during 25 surgeries, achieving a diagnostic turnaround time of less than 90 min. Of these, 18 (72%) diagnoses were correct and 7 did not reach the required confidence threshold. We conclude that machine-learned diagnosis based on low-cost intraoperative sequencing can assist neurosurgical decision-making, potentially preventing neurological comorbidity and avoiding additional surgeries.

Characterizing the tumor immune microenvironment of ependymomas using targeted gene expression profiles and RNA sequencing.

BACKGROUND: Defining the tumor immune microenvironment (TIME) of patients using transcriptome analysis is gaining more popularity. Here, we examined and discussed the pros and cons of using RNA sequencing for fresh frozen samples and targeted gene expression immune profiles (NanoString) for formalin-fixed, paraffin-embedded (FFPE) samples to characterize the TIME of ependymoma samples. RESULTS: Our results showed a stable expression of the 40 housekeeping genes throughout all samples. The Pearson correlation of the endogenous genes was high. To define the TIME, we first checked the expression of the PTPRC gene, known as CD45, and found it was above the detection limit in all samples by both techniques. T cells were identified consistently using the two types of data. In addition, both techniques showed that the immune landscape was heterogeneous in the 6 ependymoma samples used for this study. CONCLUSIONS: The low-abundant genes were detected in higher quantities using the NanoString technique, even when FFPE samples were used. RNA sequencing is better suited for biomarker discovery, fusion gene detection, and getting a broader overview of the TIME. The technique that was used to measure the samples had a considerable effect on the type of immune cells that were identified. The limited number of tumor-infiltrating immune cells compared to the high density of tumor cells in ependymoma can limit the sensitivity of RNA expression techniques regarding the identification of the infiltrating immune cells.

Pleuropulmonary blastoma (PPB) and other DICER1-associated high-grade malignancies are morphologically, genetically and epigenetically related - A comparative study of 4 PPBs and 6 sarcomas.

DICER1-related tumors occur hereditary or sporadically, with high-grade malignancies sharing clinicopathological and (epi)genetic features. We compared 4 pleuropulmonary blastomas (PPBs) and 6 sarcomas by mutation analysis, whole transcriptome sequencing and methylation profiling. 9/10 patients were female. PPB patients were 0-4 years. 3/4 were alive; 2 without disease. One patient died of metastatic disease (median follow-up, 16 months). Sarcoma patients were 16-56 years. Locations included: uterine cervix/corpus (3/1), soft tissue back/shoulder (1) and paravertebral (1). 5/6 patients were alive; 2 developed metastases: intracranial (1) and lung and kidney (1) (median follow-up, 17 months). The deceased patient previously had a PPB and a Sertoli-Leydig cell tumor. Histologically, tumors showed atypical primitive-looking cells with incomplete rhabdomyoblastic differentiation and cartilage (n = 5). Immunohistochemistry demonstrated desmin- (n = 9/10), myogenin- (n = 6/10) and keratin positivity (n = 1/1). Eight cases harbored biallelic DICER1 mutations with confirmed germline mutations in 4 cases. Two cases showed a monoallelic mutation. By RNA expression- and methylation profiling, distinct clustering of our cases was seen demonstrating a close relationship on (epi)genetic level and similarities to embryonal rhabdomyosarcoma. In conclusion, this study shows overlapping morphological, immunohistochemical and (epi)genetic features of PPBs and DICER1-associated high-grade sarcomas, arguing that these neoplasms form a spectrum with a broad clinicopathological range.

Infantile fibrosarcoma with an EGFR kinase domain duplication: Underlining a close relationship with congenital mesoblastic nephroma and highlighting a similar morphological spectrum.

Infantile fibrosarcoma (IFS) and congenital mesoblastic nephroma (CMN) are locally aggressive tumors primarily occurring in infants. Both IFS and the cellular subtype of CMN show overlapping morphological features and an ETV6-NTRK3 fusion, suggesting a close relationship. An activating alteration of EGFR, based on an EGFR kinase domain duplication (KDD), occurs in a subset of CMNs lacking an NTRK3 rearrangement, especially in the classic and mixed type. So far no EGFR-KDDs have been detected in IFS. We describe four pediatric tumors at the extremities (leg, n = 2; foot and arm n = 1) with histological features of IFS/CMN. Two cases showed classic IFS morphology while two were similar to classic/mixed type CMN. In all cases, an EGFR-KDD was identified without detection of a fusion gene. There were no abnormalities of the kidneys in any of the patients. This is the first description of IFS with an EGFR-KDD as driver mutation, supporting that IFS and CMN are similar lesions with the same morphological and genetic spectrum. Pathologists should be aware of the more fibrous variant of IFS, similar to classic/mixed type CMN. Molecular analyses are crucial to treat these lesions adequately, especially with regard to the administration of tyrosine kinase inhibitors.

The impact of turnover among respiratory care practitioners in a health care system: frequency and associated costs.

BACKGROUND: Retention of respiratory therapists (RTs) is a desired institutional goal that reflects department loyalty and RTs' satisfaction. When RTs leave a department, services are disrupted and new therapists must undergo orientation and training, which requires time and expense. Despite the widely shared goal of minimal turnover, neither the annual rate nor the associated expense of turnover for RTs has been described. STUDY PURPOSE: Determine the rate of RT turnover and the costs related to training new staff members. METHODS: The Cleveland Clinic Health System is composed of 9 participating hospitals, which range from small, community-based institutions to large, tertiary care institutions. To elicit information about annual turnover among RTs throughout the system, we conducted a survey of key personnel in each of the hospitals' respiratory therapy departments. To calculate the costs of training, we reviewed the training schedule for an RT joining the Respiratory Therapy Section at the Cleveland Clinic Hospital. Cost estimates reflect the duration of training by various supervisory RTs, their respective wages (including benefit costs), and educational materials used in training and orientation. RESULTS: Turnover rates ranged from 3% to 18% per year. Five of the 8 institutions from which rates were available reported rates greater than 8% per year. The rate of annual turnover correlated significantly with the ratio of hospital beds to RT staff (Pearson r = 0.784, r(2) = 0.61, p = 0.02). The cost of training an RT at the Cleveland Clinic Hospital totaled $3,447.11. CONCLUSIONS: Turnover among respiratory therapists poses a substantial problem because of its frequency and expense. Greater attention to issues affecting turnover and to enhancing retention of RTs is warranted.

Cost impact of metered dose inhalers vs small volume nebulizers in hospitalized patients: the Cleveland Clinic experience.

To assess the cost impact of using metered dose inhalers (MDIs) versus small volume nebulizers (SVNs) for hospitalized adult patients not being managed in ICUs, we analyzed the labor, equipment, and medication costs associated with using MDIs at The Cleveland Clinic Foundation. Over the study interval (January 1988-December 1989), a policy was implemented to enhance MDI use, resulting in increased use of MDIs (18% of all bronchodilator treatments in 1989 vs 5% in 1988). Based on a volume of approximately 70,000 bronchodilator treatments/year in our hospital, increased MDI use with this policy reduced direct costs by $26,510, with associated savings in respiratory-therapist time. To extend this analysis of costs to other institutional settings, we present an analysis of projected changes in institutional costs when the volume of bronchodilator therapies and the percentage administered by MDI varies.

Physician-ordered respiratory care vs physician-ordered use of a respiratory therapy consult service: early experience at The Cleveland Clinic Foundation.

BACKGROUND: Accumulative evidence suggests that respiratory care is frequently misallocated. We report the results of a pilot study of a delivery system aimed at correcting such misallocation. METHODS: The delivery system (Respiratory Therapy Consult Service, or RTCS) allows respiratory therapists (when requested by the case-managing physician) to determine respiratory care, with decisions guided by algorithm (ie, Consult patients). In the pilot study, Therapist Evaluators responded to requests for Consults on two study wards. All staff therapists participated in implementing Evaluator-determined treatment. STUDY DESIGN: We evaluated 38 patients (20 of whom were Consult patients) randomly selected from a total of 82 patients undergoing abdominal surgery during the study period. RESULTS: Consult patients were significantly older than non-Consult patients, more likely to be heavy smokers (67 vs 43%), and sicker as suggested by a higher Triage Score. Consult patients received more types and more total respiratory care services, demonstrated a trend toward longer stay, and had significantly higher respiratory therapy charges. CONCLUSION: Our experience shows that a consult program can be successfully implemented in a large, tertiary care institution with widespread physician and nursing support. Whether the RTCS fulfills its goal of ameliorating misallocation of respiratory care has yet to be proven and awaits the completion of other studies currently under way.

Pulmonary edema of environmental origin--newer concepts.

Pulmonary edema of non-cardiac origin is usually an urgent clinical problem, which has recently increased in frequency throughout the world in the past few years. This is partly due to sociological factors and to pre-eminent advances in industrial technology. Recent severe massive toxic gas explosions have had national and worldwide implications. Therefore, urgent and appropriate therapy is of utmost importance in most of these patients. The use of high flow oxygen with Constant Positive Pressure Breathing are the main inhalational therapeutic approaches. Newer modalities of treatment include: (1) earlier Fiberoptic bronchoscopy in those individuals afflicted with aspiration problems and (2) certain specific chemical blocking agents for the management of phosgene intoxication and hydrogen sulfide toxicity. Preventive environmental measures are also important.

Ordering respiratory care services for hospitalized patients: practices of overuse and underuse.

Because of recent concerns about misallocation of respiratory care services and analyses suggesting that limiting services to comply with established guidelines reduces unneeded therapies without compromising quality of care, the authors audited the records of 170 patients newly ordered to receive at least one of five respiratory therapies (oxygen therapy, incentive spirometry, bronchopulmonary hygiene, aerosolized bronchodilator therapy, or intermittent positive pressure breathing) at The Cleveland Clinic Foundation. In reviewing whether the therapies that were ordered complied with published guidelines for these services, we found that 25.2% were "not indicated." This over-ordering incurred unnecessary total charges of $11,937 ($206.16 per patient) and occupied therapist time that could have been better allocated to other services. These costs were offset by the finding that 10.5% of the patients were not ordered to receive indicated respiratory therapies. Our proposed strategy of initiating protocols for ordering and providing respiratory care services (ie, via a respiratory care consult service) is an appealing means to address this misallocation, but it requires further evaluation.

Constructing a therapist-driven protocol. Spectrum of types and quality control.

Therapist-driven protocols for the implementation and delivery of respiratory care must be tailored to fit the needs of the individual institution. The method that is chosen for constructing a therapist-driven protocol depends on the type of protocol desired (disease-, symptom-, or treatment-based) and on whether a narrative or flow-diagram format is preferred. Because the goal of therapist-driven protocols is to provide a systematic method for determining appropriate respiratory care, quality control measures are necessary to ensure that desired outcomes are achieved. Quality control monitoring can be performed through the use of case-study exercises, verbal shift reports, and care-plan audits. Results of quality control monitoring techniques can be used to guide modification of protocols.

Organisation, regulations, preparation and logistics of parenteral nutrition in hospitals and homes; the role of the nutrition support team - Guidelines on Parenteral Nutrition, Chapter 8.

PN (parenteral nutrition) should be standardised to ensure quality and to reduce complications, and it should be carried out in consultation with a specialised nutrition support team whenever possible. Interdisciplinary nutrition support teams should be established in all hospitals because effectiveness and efficiency in the implementation of PN are increased. The tasks of the team include improvements of quality of care as well as enhancing the benefit to cost ratio. Therapeutic decisions must be taken by attending physicians, who should collaborate with the nutrition support team. "All-in-One" bags are generally preferred for PN in hospitals and may be industrially manufactured, industrially manufactured with the necessity to add micronutrients, or be prepared "on-demand" within or outside the hospital according to a standardised or individual composition and under consideration of sterile and aseptic conditions. A standardised procedure should be established for introduction and advancement of enteral or oral nutrition. Home PN may be indicated if the expected duration of when PN exceeds 4 weeks. Home PN is a well established method for providing long-term PN, which should be indicated by the attending physician and be reviewed by the nutrition support team. The care of home PN patients should be standardised whenever possible. The indication for home PN should be regularly reviewed during the course of PN.

Respiratory care protocols in the Cleveland Clinic Health System.

Although respiratory care protocols have been proven efficacious in several academic medical centers, little attention has been given to their use and effect in community-based hospitals. To evaluate the use and effect of respiratory care protocols in community hospitals in the Cleveland Clinic Health System (CCHS) in Cleveland, OH, an observational study was conducted based on a survey of respiratory therapists from 9 of the 10 CCHS hospitals. Study results showed that respiratory care protocols had been implemented in most of the CCHS hospitals in a variety of formats and that use of a full respiratory therapy consult service was common. Over-ordering of respiratory care services was reported far more frequently than was under-ordering and was often the impetus to adopt respiratory care protocols. Larger hospitals were more likely to implement protocols, but protocol use was not associated with having a residency training program. Furthermore, in the three hospitals in which the issue was examined, use of respiratory care protocols did not appear to discourage pulmonary consultation. As was the case in academic medical centers, which have generated most studies to date, the use of respiratory care protocols was reported to be beneficial in community-based hospitals.

Respiratory care protocols in postanesthesia care.

Respiratory care protocols have been developed for specific therapies that include the following: oxygen titration, weaning from mechanical ventilation, sampling arterial blood gases, managing bronchospasm and secretions, treating atelectasis, endotracheal extubation, and managing the postextubation airway. Although relatively little attention has been given to using protocols in postanesthesia care, this environment lends itself to applying protocols. In this context, studies have examined and support the use of protocols for titrating supplemental oxygen, weaning patients from mechanical ventilation, and sampling arterial blood gases. As with other previously mentioned respiratory protocols, these protocols have shown efficacy for improving allocation of respiratory care services, cost savings, and favorable clinical outcomes. On this basis, while recognizing the need for further studies, respiratory care protocols implemented by respiratory therapists can be beneficial in the postanesthesia care setting.

Randomized controlled trial of physician-directed versus respiratory therapy consult service-directed respiratory care to adult non-ICU inpatients.

Although current evidence suggests that respiratory care protocols can enhance allocation of respiratory care services while conserving costs, a randomized trial is needed to address shortcomings of available studies. We therefore conducted a randomized controlled trial comparing respiratory care for adult non-ICU inpatients directed by a Respiratory Therapy Consult Service (RTCS) versus respiratory care by managing physicians. Eligible subjects were adult non-ICU inpatients whose physicians had prescribed specific respiratory care services. Consecutive eligible patients were approached for consent, after which a blocked randomization strategy was used to assign patients to (1) Physician-directed respiratory care, in which the prescribed physician respiratory care orders were maintained (n = 74), or (2) RTCS-directed respiratory care, in which the physician's respiratory care orders were preempted by a respiratory care plan generated by the RTCS (n = 71). Specifically, these patients were evaluated by an RTCS therapist evaluator whose respiratory care plan was based on sign/symptom-based algorithms drafted to comply with the American Association for Respiratory Care (AARC) Clinical Practice Guidelines. Appropriateness of respiratory care orders was assessed as agreement between the prescribed respiratory care plan and an algorithm-based "standard care plan" generated by an expert therapist who was blind to the patient's actual orders. The compared groups were similar at baseline regarding demographic features, admission diagnostic category, smoking status, and Triage Score (mean, 3.8 +/- 0.9 SD [RTCS] versus 3.7 +/- 1.0). Similarly, no differences were observed between RTCS-directed and physician-directed respiratory care regarding hospital mortality rate (5.7 versus 5.6%), hospital length of stay (7.9 +/- 9.0 versus 7.7 +/- 7.3 d), total number of respiratory care treatments delivered (30.3 +/- 30 versus 31.6 +/- 30.5), or days requiring respiratory care (4.2 +/- 5.2 versus 4.1 +/- 3.6). Notably, using both a stringent (S) and a liberal (L) criterion for agreement, RTCS-directed respiratory care demonstrated better agreement with the "standard care plan" (82 +/- 17% [S] and 86 +/- 16% [L]) than did physician-directed respiratory care (64 +/- 21% [S] and 72 +/- 23% [L]) (p < 0.001). Finally, the true cost of respiratory care treatments was slightly lower with RTCS-directed respiratory care (mean, $235.70 versus $255.70/pt, p = 0.61). We conclude that (1) compared with physician-directed respiratory care, the RTCS prescribed a similar number and duration of respiratory care services at a slight savings (that did not achieve statistical significance) and without any increased adverse events; and (2) compared with physician-directed respiratory care, RTCS-directed respiratory care showed greater agreement with Clinical Practice Guideline-based algorithms.