Targeted therapy for non-small cell lung cancer.

The treatment of advanced non-small cell lung cancer has been with systemic chemotherapy and usually consists of a platinum doublet chemotherapy. The identification of somatic driver mutations has resulted in new drugs that target these mutations. This report discusses the two most important new targeted therapy drugs for the treatment of advanced non-small cell lung cancer that have these driver mutations.

A Phase II study of pulse dose imatinib mesylate and weekly paclitaxel in patients aged 70 and over with advanced non-small cell lung cancer.

BACKGROUND: In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR). METHODS: This single-stage, open-label phase II study evaluated pulse dose imatinib and weekly paclitaxel in elderly patients with advanced NSCLC. Eligible patients were aged ≥ 70 with untreated, stage IIIB-IV NSCLC and ECOG performance status 0-2. Primary endpoint was RR. Secondary endpoints included median progression free and overall survival (PFS, OS) and correlatives of PDGFR pathway activation. Baseline Charlson Comorbidity Index (CCI) and Vulnerable Elder Survey-13 (VES-13) were correlated with outcomes. RESULTS: Thirty-four patients with median age 75 enrolled. Eleven of 29 (38%) were frail by VES-13 score. Overall RR was 11/34 (32%; 95% CI 17%-51%), meeting the primary endpoint. Median PFS and OS were 3.6 and 7.3 months, respectively. High tumoral PDGF-B expression predicted inferior PFS. Frail patients by VES-13 had significantly worse median PFS (3.2 vs. 4.5 months; p=0.02) and OS (4.8 vs. 12 months; p=0.02) than non-frail. CONCLUSIONS: The combination of imatinib and paclitaxel had encouraging activity as measured by the primary endpoint of RR. However, PFS and OS were typical for elderly patients treated with single agent chemotherapy and the regimen is not recommended for further study. Adjunct imatinib did not overcome the established association of tumoral PDGF-B expression with inferior PFS. VES-13 was a powerful predictor of poor survival outcomes. Frailty should be further studied as a predictor of non-benefit from chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01011075.

Improvement in Stage of Lung Cancer Diagnosis With Incidental Pulmonary Nodules Followed With a Patient Tracking System and Computerized Registry.

Introduction: Given that an incidental pulmonary nodule (IPN) on chest computed tomography (CT) may represent nascent lung cancer, timely follow-up imaging is critical to assess nodule growth and the need for tissue sampling. We previously reported our institution's systematic process to identify and track patients with an IPN associated with improved CT on follow-up. We hypothesized that this improvement may have led to a higher frequency of early-stage lung cancer. To evaluate this, we performed a study to determine whether cases of early-stage lung cancer were more likely to have had our tracking system applied to suspicious findings. Methods: An observational study was performed by identifying cases of lung cancer that were detected as IPNs on chest CT scans performed at our institution, from 2006 to 2016. A total of 314 cases were dichotomized into early-stage (stage 1) or late-stage (stages II to IV) disease. A multivariant regression analysis with modeling was used to determine factors associated with a diagnosis of early-stage disease. Factors included the use of the tracking system and nodule registry. Results: The following factors were independently associated with early-stage lung cancer: index nodule diameter, (OR = 0.971, confidence interval [CI]: 0.948-0.995], p = 0.016), adenocarcinoma histology (OR = 2.930 [CI: 1.695-5.064], p = 0.0001) and use of tracker phrases on CT reports (OR = 1.939 [CI: 1.126-3.339], p = 0.016). Conclusions: The application of a patient tracking system and computerized lung nodule registry lead to an increased frequency in the diagnosis of stage 1 NSCLC from IPNs. This is a meaningful outcome for patients and should be adapted for IPN management.

Impact of early detection on cancer curability: A modified Delphi panel study.

Expert consensus on the potential benefits of early cancer detection does not exist for most cancer types. We convened 10 practicing oncologists using a RAND/UCLA modified Delphi panel to evaluate which of 20 solid tumors, representing >40 American Joint Committee on Cancer (AJCC)-identified cancer types and 80% of total cancer incidence, would receive potential clinical benefits from early detection. Pre-meeting, experts estimated how long cancers take to progress and rated the current curability and benefit (improvement in curability) of an annual hypothetical multi-cancer screening blood test. Post-meeting, experts rerated all questions. Cancers had varying estimates of the potential benefit of early cancer detection depending on estimates of their curability and progression by stage. Cancers rated as progressing quickly and being curable in earlier stages (stomach, esophagus, lung, urothelial tract, melanoma, ovary, sarcoma, bladder, cervix, breast, colon/rectum, kidney, uterus, anus, head and neck) were estimated to be most likely to benefit from a hypothetical screening blood test. Cancer types rated as progressing quickly but having comparatively lower cure rates in earlier stages (liver/intrahepatic bile duct, gallbladder, pancreas) were estimated to have medium likelihood of benefit from a hypothetical screening blood test. Cancer types rated as progressing more slowly and having higher curability regardless of stage (prostate, thyroid) were estimated to have limited likelihood of benefit from a hypothetical screening blood test. The panel concluded most solid tumors have a likelihood of benefit from early detection. Even among difficult-to-treat cancers (e.g., pancreas, liver/intrahepatic bile duct, gallbladder), early-stage detection was believed to be beneficial. Based on the panel consensus, broad coverage of cancers by screening blood tests would deliver the greatest potential benefits to patients.

Improvement in Follow-up Imaging With a Patient Tracking System and Computerized Registry for Lung Nodule Management.

PURPOSE: Despite established guidelines, radiologists' recommendations and timely follow-up of incidental lung nodules remain variable. To improve follow-up of nodules, a system using standardized language (tracker phrases) recommending time-based follow-up in chest CT reports, coupled with a computerized registry, was created. MATERIALS AND METHODS: Data were obtained from the electronic health record and a facility-built electronic lung nodule registry. We evaluated two randomly selected patient cohorts with incidental nodules on chest CT reports: before intervention (September 2008 to March 2011) and after intervention (August 2011 to December 2016). Multivariable logistic regression was used to compare the cohorts for the main outcome of timely follow-up, defined as a subsequent report within 13 months of the initial report. RESULTS: In all, 410 patients were included in the pretracker cohort versus 626 in the tracker cohort. Before system inception, 30% of CT reports lacked an explicit time-based recommendation for nodule follow-up. The proportion of patients with timely follow-up increased from 46% to 55%, and the proportion of those with no documented follow-up or follow-up beyond 24 months decreased from 48% to 31%. The likelihood of timely follow-up increased 41%, adjusted for high risk for lung cancer and age 65 years or older. After system inception, reports missing a tracker phrase for nodule recommendation averaged 6%, without significant interyear variation. CONCLUSIONS: Standardized language added to CT reports combined with a computerized registry designed to identify and track patients with incidental lung nodules was associated with improved likelihood of follow-up imaging.

Adaptive Fluorodeoxyglucose-Positron Emission Tomography Based Chemotherapy Selection for Metastatic Non-small Cell Lung Cancer.

Objectives The change in tumor fluorodeoxyglucose (FDG) uptake by positron emission tomography (PET) scan after one cycle of platinum-based chemotherapy has been shown to predict progression-free and overall survival (PFS and OS) among advanced non-small cell lung cancer (NSCLC) patients. Using early FDG-PET response to determine subsequent chemotherapy, we aim to evaluate the role that adaptive chemotherapy regimens have on later CT response, PFS, and OS in patients with advanced NSCLC. Materials and Methods Chemotherapy-naïve patients with metastatic NSCLC received carboplatin and paclitaxel (CP) on day one and repeated FDG-PET on day 18. PET-responding patients continued CP chemotherapy for a total of four cycles. PET non-responders were switched to alternate docetaxel and gemcitabine (DG) for three additional cycles. The primary outcome was the CT Response Evaluation Criteria in Solid Tumors (RECIST 1.0) response. Secondary endpoints included PFS and OS. Results  Forty-six patients initiated treatment with chemotherapy on trial and were evaluable by PET/CT. Of these, 19 (41%) met the FDG-PET criteria for the response after a single cycle of CP. Only one non-responding patient had a CT response. Despite the lack of CT response in the DG arm, no trend for worse PFS or OS was seen between the two arms. Conclusions This work demonstrates that changing chemotherapy in the event of non-response by PET did not lead to improved CT RECIST response. However, non-responding patients who switched chemotherapy had similar PFS and OS to those who responded by PET and continued the same regimen.

Clinical utility of routine proteinuria evaluation in treatment decisions of patients receiving bevacizumab for metastatic solid tumors.

BACKGROUND: Bevacizumab is an anti-vascular endothelial growth factor monoclonal antibody approved for use in treatment of patients with metastatic breast, colorectal, and non-small cell lung cancer. In the pivotal Phase 3 clinical trials, grades 3-4 proteinuria occurred in <5% of patients. The manufacturer recommends monitoring for the development of proteinuria but does not provide specific recommendations, except to discontinue treatment if the patient develops nephrotic syndrome. OBJECTIVE: To determine the incidence and severity of elevated proteinuria and the frequency of changes in bevacizumab administration due to elevated proteinuria; secondary objectives included analysis of the cost of routine proteinuria monitoring and the relationship of proteinuria with other patient comorbidities such as diabetes, hypertension, chronic kidney disease, and viral hepatitis. METHODS: A retrospective chart review was performed at the University of Washington Medical Center, a large academic teaching hospital, and its affiliated ambulatory clinics at the Seattle Cancer Care Alliance. Patients treated with bevacizumab and seen in the breast, lung, and gastrointestinal cancer clinics from June 1, 2005, to November 30, 2007, were included in the study. RESULTS: A total of 243 patients were included in the analysis. Only 1.6% of these patients developed grades 3-4 proteinuria. All 4 of these patients had a history of hypertension, 2 of these patients had prior chronic kidney disease, and 3 patients had prior viral hepatitis. Elevated proteinuria affected treatment decisions in 2% of patients. Over $130,000 was charged to patients for monitoring of proteinuria. CONCLUSIONS: These results demonstrate that the development of grades 3-4 proteinuria with bevacizumab is rare and affects treatment decisions in few patients with metastatic solid tumor. Furthermore, routine proteinuria monitoring is associated with high cost and may not be required before each administration.

Cognitive control and attentional selection in adolescents with ADHD versus ADD.

An important research question is whether Attention Deficit Hyperactivity Disorder (ADHD) is related to early- or late-stage attentional control mechanisms and whether this differentiates a nonhyperactive subtype (ADD). This question was addressed in a sample of 145 ADD/ADHD and typically developing comparison adolescents (aged 13-17). Attentional blink and antisaccade tasks were used to assay early- and late-stage control, respectively. ADD was defined using normative cutoffs to ensure low activity level in children who otherwise met full criteria for ADHD. The ADD group had an attenuated attentional blink versus controls and ADHD-combined. The effect was not produced using DSM--IV definition of ADHD-primarily inattentive type or DSM symptom counts. ADHD-combined showed greater weakness in response inhibition, as manifest in the antisaccade task. Combining tasks yielded an interaction differentiating group performance on the two tasks.

Identification of Nonaggressive Pulmonary Nodules Using an Optimized Scoring System.

PURPOSE: The purpose of this study was to define the optimal scoring method for identifying benign intrapulmonary lymph nodes. MATERIALS AND METHODS: Subjects for this study were selected from the COPDGene study, a large multicenter longitudinal observational cohort study. A retrospective case-control analysis was performed using identified nodules on a subset of 377 patients who demonstrated 765 pulmonary nodules on their baseline computed tomography (CT) study. Nodule characteristics of 636 benign nodules (which resolved or showed <20% growth rate at 5 y follow-up) were compared with 51 nodules that occurred in the same lobe as a reported malignancy. Two radiologists scored each pulmonary nodule on the basis of intrapulmonary lymph node characteristics. A simple scoring strategy weighing all characteristics equally was compared with an optimized scoring strategy that weighed characteristics on the basis of their relative importance in identifying benign pulmonary nodules. RESULTS: A total of 479 of 636 benign pulmonary nodules had the majority of lymph node characteristics, whereas only 1 subpleural nodule with the majority of lymph node characteristics appeared to be malignant. Only 279 of 479 (58%) of benign pulmonary nodules with the majority of lymph node characteristics were intrafissural or subpleural. The optimized scoring strategy showed improved performance compared with the simple scoring strategy with average area under the curve of 0.80 versus 0.55. Optimized cutoff scores showed negative likelihood values for both readers of <0.2. A simulation showed a potential reduction in CT utilization of up to 36% for Fleischner criteria and up to 5% for LUNG-RADS. CONCLUSIONS: Nodules with the majority of lymph node characteristics, regardless of location, are likely benign, and weighing certain lymph node characteristics greater than others can improve overall performance. Given the potential to reduce CT utilization, lymph node characteristics should be considered when recommending appropriate follow-up.

Machine learning approach for distinguishing malignant and benign lung nodules utilizing standardized perinodular parenchymal features from CT.

PURPOSE: Computed tomography (CT) is an effective method for detecting and characterizing lung nodules in vivo. With the growing use of chest CT, the detection frequency of lung nodules is increasing. Noninvasive methods to distinguish malignant from benign nodules have the potential to decrease the clinical burden, risk, and cost involved in follow-up procedures on the large number of false-positive lesions detected. This study examined the benefit of including perinodular parenchymal features in machine learning (ML) tools for pulmonary nodule assessment. METHODS: Lung nodule cases with pathology confirmed diagnosis (74 malignant, 289 benign) were used to extract quantitative imaging characteristics from computed tomography scans of the nodule and perinodular parenchyma tissue. A ML tool development pipeline was employed using k-medoids clustering and information theory to determine efficient predictor sets for different amounts of parenchyma inclusion and build an artificial neural network classifier. The resulting ML tool was validated using an independent cohort (50 malignant, 50 benign). RESULTS: The inclusion of parenchymal imaging features improved the performance of the ML tool over exclusively nodular features (P < 0.01). The best performing ML tool included features derived from nodule diameter-based surrounding parenchyma tissue quartile bands. We demonstrate similar high-performance values on the independent validation cohort (AUC-ROC = 0.965). A comparison using the independent validation cohort with the Fleischner pulmonary nodule follow-up guidelines demonstrated a theoretical reduction in recommended follow-up imaging and procedures. CONCLUSIONS: Radiomic features extracted from the parenchyma surrounding lung nodules contain valid signals with spatial relevance for the task of lung cancer risk classification. Through standardization of feature extraction regions from the parenchyma, ML tool validation performance of 100% sensitivity and 96% specificity was achieved.

Does age influence loss of heterozygosity?

The striking correlation between advanced age and an increased incidence of cancer has led investigators to examine the influence of aging on genome maintenance. Because loss of heterozygosity (LOH) can lead to the inactivation of tumor suppressor genes, and thus carcinogenesis, understanding the affect of aging on this type of mutation event is particularly important. Several factors may affect the rate of LOH, including an increase in the amount of DNA damage, specifically double-strand breaks (DSBs), and the ability to efficiently repair this damage via pathways that minimize the loss of genetic information. Because of experimental constraints, there is only suggestive evidence for a change in the rate of DNA damage as humans age. However, recent studies in model organisms find that there are increased rates of LOH with age, and that repair of DNA damage occurs via a different pathway in old cells versus young cells. We speculate that the age-dependent change in DNA repair may explain why there is increased LOH, and that the findings from these model organisms may extend to humans.

Cognitive inhibition and working memory in attention-deficit/hyperactivity disorder.

Studies of cognitive control in attention-deficit/hyperactivity disorder (ADHD) have emphasized the ability to suppress motor responses (i.e., behavioral inhibition) rather than the ability to actively suppress prepotent mental representations (i.e., cognitive inhibition). Further, working memory deficits are suspected in ADHD, yet their distinction from cognitive inhibition is unclear. Two hundred and eighty-eight adolescent and adult participants, 115 of whom met criteria for ADHD and 173 of whom were for non-ADHD comparison, completed a sentence processing task that required the suppression of an incorrect interpretation and a working memory task. The results failed to support cognitive inhibition problems in ADHD. Moreover, the ability to reanalyze sentences with a temporary misinterpretation was at least partially related to working memory performance. The results challenge a unitary inhibition problem in ADHD and suggest inhibition problems do not extend to cognitive suppression in this age range.

Features of COPD as Predictors of Lung Cancer.

BACKGROUND: Lung cancer is a leading cause of death and hospitalization for patients with COPD. A detailed understanding of which clinical features of COPD increase risk is needed. METHODS: We performed a nested case-control study of Genetic Epidemiology of COPD (COPDGene) Study subjects with and without lung cancer, age 45 to 80 years, who smoked at least 10-pack years to identify clinical and imaging features of smokers, with and without COPD, that are associated with an increased risk of lung cancer. The baseline evaluation included spirometry, high-resolution chest CT scanning, and respiratory questionnaires. New lung cancer diagnoses were identified over 8 years of longitudinal follow-up. Cases of lung cancer were matched 1:4 with control subjects for age, race, sex, and smoking history. Multiple logistic regression analyses were used to determine features predictive of lung cancer. RESULTS: Features associated with a future risk of lung cancer included decreased FEV1/FVC (OR, 1.28 per 10% decrease [95% CI, 1.12-1.46]), visual severity of emphysema (OR, 2.31, none-trace vs mild-advanced [95% CI, 1.41-3.86]), and respiratory exacerbations prior to study entry (OR, 1.39 per increased events [0, 1, and ≥ 2] [95% CI, 1.04-1.85]). Respiratory exacerbations were also associated with small-cell lung cancer histology (OR, 3.57 [95% CI, 1.47-10]). CONCLUSIONS: The degree of COPD severity, including airflow obstruction, visual emphysema, and respiratory exacerbations, was independently predictive of lung cancer. These risk factors should be further studied as inclusion and exclusion criteria for the survival benefit of lung cancer screening. Studies are needed to determine if reduction in respiratory exacerbations among smokers can reduce the risk of lung cancer.

Attentional versus motor inhibition in adults with attention-deficit/hyperactivity disorder.

Faulty inhibition is theorized to be a central feature in attention-deficit/hyperactivity disorder (ADHD), but it remains unclear whether inhibitory impairments encompass both motoric and attentional domains. Further, characterization of inhibitory deficits in adults with ADHD is needed. We experimentally assessed adults who met diagnostic criteria for ADHD and a subgroup who had partially remitted. Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) subtype effects were also examined. Motoric inhibition was assessed with the antisaccade task, and attentional inhibition was assessed with the attentional blink (AB) task. Antisaccade results replicated prior findings of extended latencies and increased anticipatory saccades in ADHD. Errors, however, appeared to be epiphenomenal to ADHD as they were absent when symptoms had partially remitted. Anticipatory saccades appeared as potential core problems that remained even when symptoms had improved. Differential response patterns were found for predominantly inattentive and combined subtypes, with the latter showing increasing anticipatory movements with increasing fixation time. In the AB task, ADHD groups committed more errors but showed no convincing evidence of an abnormal blink. These results demonstrate clear effects on motoric inhibition but not attentional inhibition in adults with ADHD.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Neuroendocrine Hyperplasia of Infancy.

Although incidental reactive pulmonary neuroendocrine cell hyperplasia (PNECH) is seen on biopsy specimens in adults with chronic lung disease, disorders characterized by marked PNECH are rare. Primary hyperplasia of neuroendocrine cells in the lung and obstructive lung disease related to remodeling or physiologic constriction of small airways define diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) in the adult and neuroendocrine cell hyperplasia of infancy (NEHI) in children. DIPENCH and NEHI share a similar physiology, typical imaging appearance, and increased neuroendocrine cells on biopsy. However, there are important differences related to the underlying disease mechanisms leading to disparate outcomes.

Development of a Cancer Care Summary Through the Electronic Health Record.

INTRODUCTION: Our objective was to improve communication concerning lung cancer patients by developing and distributing a Cancer Care Summary that would provide clinically useful information about the patient's diagnosis and care to providers in diverse settings. METHODS: We designed structured, electronic forms for the electronic health record (EHR), detailing tumor staging, classification, and treatment. To ensure completeness and accuracy of the information, we implemented a data quality cycle, composed of reports that are reviewed by oncology clinicians. The data from the EHR forms are extracted into a structured query language database system on a daily basis, from which the Summaries are derived. We conducted focus groups regarding the utility, format, and content of the Summary. Cancer Care Summaries are automatically generated 4 months after a patient's date of diagnosis, then every 6 months for those receiving treatment, and on an as-needed basis for urgent care or hospital admission. RESULTS: The product of our improvement project is the Cancer Care Summary. To date, 102 individual patient Summaries have been generated. These documents are automatically entered into the National Jewish Health (NJH) EHR, attached to correspondence to primary care providers, available to patients as electronic documents on the NJH patient portal, and faxed to emergency departments and admitting physicians on patient evaluation. CONCLUSION: We developed a sustainable tool to improve cancer care communication. The Cancer Care Summary integrates information from the EHR in a timely manner and distributes the information through multiple avenues.

Malignant pleural disease is highly associated with subsequent peritoneal metastasis in patients with stage IV non-small cell lung cancer independent of oncogene status.

INTRODUCTION: Peritoneal metastasis from lung cancer is an uncommon clinical event and there are limited data on what factors predict peritoneal progression. This study retrospectively investigated whether patterns of metastatic spread and oncogene status in patients with advanced non-small cell lung cancer (NSCLC) are associated with peritoneal metastasis. METHODS: Patients with metastatic non-squamous NSCLC (n=410) were identified at the University of Colorado Cancer Center. Sites of metastatic disease and baseline oncogene status (EGFR, ALK, KRAS, or triple negative) were documented via a retrospective chart review. In patients with EGFR mutations who developed peritoneal disease, we documented the presence of known resistance mechanisms. Median time to peritoneal metastasis, time from peritoneal disease to death, and overall survival were collected. RESULTS: Eight percent (33/410) patients in this study developed peritoneal metastasis. Malignant pleural disease at baseline was significantly associated with subsequent peritoneal spread. There was no association between oncogene status and peritoneal metastasis. Three patients with EGFR mutations who developed peritoneal metastasis had documented resistance to tyrosine kinase inhibitors (TKIs) in the ascitic fluid. Median time from stage IV disease to peritoneal metastasis was 16.5 months (range 0.6-108 months). There were no differences in overall survival between patients who developed peritoneal metastasis and those who did not. CONCLUSIONS: Malignant pleural disease is highly associated with peritoneal metastasis in patients with advanced NSCLC. The underlying mechanism is not clear. The presence of resistance mutations in ascitic fluid implies that poor drug penetration is unlikely to be the dominant mechanism. Despite being a late clinical finding, there were no differences in overall survival between patients who developed peritoneal metastasis and those who did not. Additional studies exploring treatment related factors in patients with malignant pleural disease that can reduce risk of peritoneal metastasis are warranted.

The clinical course of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.

BACKGROUND: Current understanding of the clinical course of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is poor and based predominantly on small case series. In our clinical experience, we have found that the diagnosis of DIPNECH is frequently delayed because respiratory symptoms are ascribed to other lung conditions. The objectives of this study were to collect and analyze longitudinal clinical data on pulmonary physiology, chest high-resolution CT (HRCT) imaging, and therapies to better delineate the course of disease. METHODS: We established a cohort of patients (N = 30) with DIPNECH seen at our institution. We used descriptive statistics to summarize cohort characteristics and longitudinal analytic techniques to model FEV1 % predicted (FEV1%) over time. RESULTS: All subjects were women who presented with long-standing cough and dyspnea. The majority had an FEV1% < 50% at the time of diagnosis. Forty percent were given a diagnosis of asthma as the cause for physiologic obstruction. The mean FEV1% for the entire cohort showed no statistically significant decline over time, but 26% of the subjects experienced a 10% decline in FEV1 within 2 years. Among the pathology samples available for review, 28% (five of 18) had typical carcinoids and 44% had associated constrictive bronchiolitis. We propose clinical diagnostic criteria for DIPNECH that incorporate demographic, pulmonary physiology, HRCT imaging, and transbronchial and surgical lung biopsy data. CONCLUSIONS: DIPNECH is a female-predominant lung disease manifested by dyspnea and cough, physiologic obstruction, and nodules on HRCT imaging. Additional research is needed to understand the natural history of this disease and validate the proposed diagnostic criteria.