A Real-World Study of Patient Characteristics and Clinical Outcomes in EGFR Mutated Lung Cancer Treated with First-Line Osimertinib: Expanding the FLAURA Trial Results into Routine Clinical Practice.

Osimertinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that is used for first-line therapy in EGFR mutated non-small cell lung cancer (NSCLC) based on the results of the randomized FLAURA trial (ClinicalTrials.gov number NCT02296125). We performed a retrospective analysis of baseline characteristics and clinical outcomes in 56 real-world patients treated with osimertinib. In total, 45% of patients were determined to be FLAURA-eligible and 55% were FLAURA-ineligible based on the published inclusion/exclusion criteria of the aforementioned trial. For clinical outcomes, the median osimertinib time to treatment discontinuation (TTD) for all patients was 16.9 months (95% CI: 12.6-35.1), whereas the median TTD was 31.1 months (95% CI: 14.9-not reached) in the FLAURA-eligible cohort and the median TTD was 12.2 months (95% CI: 8.1-34.6 months) in the FLAURA-ineligible cohort. Re-biopsy at acquired resistance disclosed both on- and off-target mechanisms. The most common therapies following osimertinib included local therapies followed by post-progression osimertinib, platinum-doublet chemotherapy with or without osimertinib, and osimertinib combinatory targeted therapies. The median overall survival for all patients was 32.0 months (95% CI: 15.7-not reached), the median survival was not reached for the FLAURA-eligible cohort, and it was 16.5 months for the FLAURA-ineligible cohort. Our data support the use of osimertinib in real-word settings and highlight the need for designing registration trials that are more inclusive of patient/disease characteristics seen in routine clinical practice. It is yet to be determined if the use of evolving first-line EGFR inhibitor combination strategies (either platinum-doublet chemotherapy plus osimertinib or amivantamab plus lazertinib) will similarly translate from clinical trials to real-word settings.

Complete pathologic response to short-course neoadjuvant alectinib in mediastinal node positive (N2) ALK rearranged lung cancer.

OBJECTIVES: Neoadjuvant therapy prior to surgical resection for locally advanced lung cancer has evolved to incorporate systemic cytotoxic chemotherapy +/- immunotherapy +/- radiotherapy. The role of neoadjuvant precision therapies remains understudied. MATERIALS AND METHODS: We report cases with major and complete pathologic responses to off-label neoadjuvant alectinib. RESULTS: A case with stage IIIA (cT1b cN2 cM0) EML4-ALK variant 3a/b lung adenocarcinoma received 6 weeks of alectinib followed by R0 left upper lobectomy with complete pathological response (ypT0 ypN0). Another case with stage IIIA (cT3 cN2 cM0) EML4-ALK variant 2 received 12 weeks of alectinib followed by R0 right middle lobectomy with a major pathologic response (ypT1a ypN0) but systemic recurrence 12 months post-operatively. CONCLUSION: Ongoing clinical trials are evaluating the role of both neoadjuvant and adjuvant ALK-directed therapy. Our cases support the completion of ongoing trials (ALINA: NCT03456076 and ALNEO: NCT05015010), and highlight the ability of second generation ALK inhibitors to induce major and complete pathologic responses in the neoadjuvant setting plus the likely role of long-term adjuvant kinase inhibitor therapy to prevent radiographic/clinical recurrence.

Tumor Treating Fields for Ovarian Carcinoma: A Modeling Study.

PURPOSE: Since the inception of tumor treating fields (TTFields) therapy as a Food and Drug Administration-approved treatment with known clinical efficacy against recurrent and newly diagnosed glioblastoma, various in silico modeling studies have been performed in an effort to better understand the distribution of applied electric fields throughout the human body for various malignancies or metastases. METHODS AND MATERIALS: Postacquisition attenuation-corrected positron emission tomography-computed tomography image data sets from 2 patients with ovarian carcinoma were used to fully segment various intrapelvic and intra-abdominal gross anatomic structures. A 3-dimensional finite element mesh model was generated and then solved for the distribution of applied electric fields, rate of energy deposition, and current density at the clinical target volumes (CTVs) and other intrapelvic and intra-abdominal structures. Electric field-volume histograms, specific absorption rate-volume histograms, and current density-volume histograms were generated, by which plan quality metrics were derived from and used to evaluate relative differences in field coverage between models under various conditions. RESULTS: TTFields therapy distribution throughout the pelvis and abdomen was largely heterogeneous, where specifically the field intensity at the CTV was heavily influenced by surrounding anatomic structures as well as its shape and location. The electric conductivity of the CTV had a direct effect on the field strength within itself, as did the position of the arrays on the surface of the pelvis and/or abdomen. CONCLUSION: The combined use of electric field-volume histograms, specific absorption rate-volume histograms, current density-volume histograms, and plan quality metrics enables a personalized method to dosimetrically evaluate patients receiving TTFields therapy for ovarian carcinoma when certain patient- and tumor-specific factors are integrated with the treatment plan.

Association of Performance Status With Survival in Patients With Advanced Non-Small Cell Lung Cancer Treated With Pembrolizumab Monotherapy.

Importance: Despite approximately 40% of patients having Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores of at least 2 in the real world, most landmark clinical trials that led to the use of pembrolizumab as standard of care in advanced non-small cell lung cancer (NSCLC) excluded this group. Objective: To evaluate whether an ECOG PS score of at least 2 at the start of therapy is associated with progression-free survival (PFS) and overall survival (OS) in advanced NSCLC treated with pembrolizumab monotherapy. Design, Setting, and Participants: This cohort study included all consecutive patients with advanced NSCLC who underwent treatment with palliative pembrolizumab monotherapy from February 2016 to October 2019 at a single academic cancer center, with data censoring on January 15, 2020. Exposures: ECOG PS score at start of therapy, with 0 and 1 indicating fully active or restricted in strenuous activity and scores of 2 and higher indicating increasing disability. Main Outcomes and Measures: PFS and OS, measured from initiation of pembrolizumab monotherapy. Results: Of 74 patients (median [range] age, 68.5 [33-87] years; 36 [48.7%] women; 53 [71.6%] White individuals) with median follow-up of 19.5 (95% CI, 13.4-27.8) months, 45 (60.8%) had an ECOG PS of 0 or 1, while 29 (39.2%) had an ECOG PS of at least 2. There were no significant differences in the baseline characteristics, except in age. Compared with patients with PS scores of 0 or 1, those with PS scores of at least 2 had significantly lower disease control rates (38 [88.4%] vs 15 [53.6%]; P = .002), shorter median PFS (7.9 [95% CI, 4.6-15.4] months vs 2.3 [95% CI, 1.8-4.8] months; P = .004), and shorter median OS (23.2 [14.0 vs 35.7] months vs 4.1 [95% CI, 2.1-6.9] months; P < .001). Among those potentially eligible for subsequent cancer-directed therapy beyond pembrolizumab monotherapy, patients in the group with PS scores of at least 2 were less likely to receive it than those with PS scores of 0 or 1 (2 [8.3%] vs 14 [45.2%]; P = .003). Multivariable adjustment for baseline characteristics confirmed ECOG PS of at least 2 as an independent risk factor for worse PFS (HR, 2.02; 95% CI, 1.09-3.74; P = .03) and worse OS (HR, 2.87; 95% CI, 1.40-5.89; P = .004). Conclusions and Relevance: In this cohort study, having an ECOG PS score of at least 2 was associated with poorer prognosis for treatment of advanced NSCLC with palliative pembrolizumab monotherapy. Further prospective studies are needed to evaluate more objective and consistent measures of functional status to facilitate identification of patients with borderline performance status who may achieve durable clinical benefit from treatment with pembrolizumab monotherapy.

Leukocytosis and Leukemia.

Leukocytosis is among the most common findings on peripheral blood smear. A wide range of causes may mediate this finding, and careful clinical and laboratory evaluation assist in differentiating between benign and malignant causes of increased white blood cell counts. In this article, various nonmalignant causes are explored, including infectious, inflammatory, autoimmune, and allergic. In addition, malignant causes of leukocytosis are discussed, including myeloproliferative disorders, acute leukemia, and chronic leukemia, as well as treatment and monitoring for patients with these diseases.

Not all analogies are created equal: Associative and categorical analogy processing following brain damage.

Current research on analogy processing assumes that different conceptual relations are treated similarly. However, just as words and concepts are related in distinct ways, different kinds of analogies may employ distinct types of relationships. An important distinction in how words are related is the difference between associative (dog-bone) and categorical (dog-cat) relations. To test the hypothesis that analogical mapping of different types of relations would have different neural instantiations, we tested patients with left and right hemisphere lesions on their ability to understand two types of analogies, ones expressing an associative relationship and others expressing a categorical relationship. Voxel-based lesion-symptom mapping (VLSM) and behavioral analyses revealed that associative analogies relied on a large left-lateralized language network while categorical analogies relied on both left and right hemispheres. The verbal nature of the task could account for the left hemisphere findings. We argue that categorical relations additionally rely on the right hemisphere because they are more difficult, abstract, and fragile, and contain more distant relationships.

Language, perception, and the schematic representation of spatial relations.

Schemas are abstract nonverbal representations that parsimoniously depict spatial relations. Despite their ubiquitous use in maps and diagrams, little is known about their neural instantiation. We sought to determine the extent to which schematic representations are neurally distinguished from language on the one hand, and from rich perceptual representations on the other. In patients with either left hemisphere damage or right hemisphere damage, a battery of matching tasks depicting categorical spatial relations was used to probe for the comprehension of basic spatial concepts across distinct representational formats (words, pictures, and schemas). Left hemisphere patients underperformed right hemisphere patients across all tasks. However, focused residual analyses using voxel-based lesion-symptom mapping (VLSM) suggest that (1) left hemisphere deficits in the representation of categorical spatial relations are difficult to distinguish from deficits in naming these relations and (2) the right hemisphere plays a special role in extracting schematic representations from richly textured pictures.

The right hemisphere in esthetic perception.

Little about the neuropsychology of art perception and evaluation is known. Most neuropsychological approaches to art have focused on art production and have been anecdotal and qualitative. The field is in desperate need of quantitative methods if it is to advance. Here, we combine a quantitative approach to the assessment of art with modern voxel-lesion-symptom-mapping methods to determine brain-behavior relationships in art perception. We hypothesized that perception of different attributes of art are likely to be disrupted by damage to different regions of the brain. Twenty participants with right hemisphere damage were given the Assessment of Art Attributes, which is designed to quantify judgments of descriptive attributes of visual art. Each participant rated 24 paintings on 6 conceptual attributes (depictive accuracy, abstractness, emotion, symbolism, realism, and animacy) and 6 perceptual attributes (depth, color temperature, color saturation, balance, stroke, and simplicity) and their interest in and preference for these paintings. Deviation scores were obtained for each brain-damaged participant for each attribute based on correlations with group average ratings from 30 age-matched healthy participants. Right hemisphere damage affected participants' judgments of abstractness, accuracy, and stroke quality. Damage to areas within different parts of the frontal parietal and lateral temporal cortices produced deviation in judgments in four of six conceptual attributes (abstractness, symbolism, realism, and animacy). Of the formal attributes, only depth was affected by inferior prefrontal damage. No areas of brain damage were associated with deviations in interestingness or preference judgments. The perception of conceptual and formal attributes in artwork may in part dissociate from each other and from evaluative judgments. More generally, this approach demonstrates the feasibility of quantitative approaches to the neuropsychology of art.

The neural basis for spatial relations.

Studies in semantics traditionally focus on knowledge of objects. By contrast, less is known about how objects relate to each other. In an fMRI study, we tested the hypothesis that the neural processing of categorical spatial relations between objects is distinct from the processing of the identity of objects. Attending to the categorical spatial relations compared with attending to the identity of objects resulted in greater activity in superior and inferior parietal cortices (especially on the left) and posterior middle frontal cortices bilaterally. In an accompanying lesion study, we tested the hypothesis that comparable areas would be necessary to represent categorical spatial relations and that the hemispheres differ in their biases to process categorical or coordinate spatial relations. Voxel-based lesion symptom mapping results were consistent with the fMRI observations. Damage to a network comprising left inferior frontal, supramarginal, and angular gyri resulted in behavioral impairment on categorical spatial judgments. Homologous right brain damage also produced such deficits, albeit less severely. The reverse pattern was observed for coordinate spatial processing. Right brain damage to the middle temporal gyrus produced more severe deficits than left hemisphere damage. Additional analyses suggested that some areas process both kinds of spatial relations conjointly and others distinctly. The left angular and inferior frontal gyrus processes coordinate spatial information over and above the categorical processing. The anterior superior temporal gyrus appears to process categorical spatial information uniquely. No areas within the right hemisphere processed categorical spatial information uniquely. Taken together, these findings suggest that the functional neuroanatomy of categorical and coordinate processing is more nuanced than implied by a simple hemispheric dichotomy.

Functional-anatomical organization of predicate metaphor processing.

The bulk of the research on the neural organization of metaphor comprehension has focused on nominal metaphors and the metaphoric relationships between word pairs. By contrast, little work has been conducted on predicate metaphors using verbs of motion such as "The man fell under her spell." We examined predicate metaphors as compared to literal sentences of motion such as "The child fell under the slide" in an event-related, functional MRI study. Our results demonstrated greater activation in the left inferior frontal cortex and left lateral temporal lobe for predicate metaphors as compared to literal sentences, while no differences were seen in homologous areas of the right hemisphere. We suggest that the results support a neural organization principle for motion processing in which greater abstraction proceeds along a posterior-to-anterior axis within the lateral portion of the left temporal cortex.

Take it to the bridge: an interhemispheric processing advantage for emotional faces.

Recent evidence indicates that emotional stimuli may be accorded special priority in information processing. Extending that research, this study tested the hypothesis that communication between the left and right hemispheres would be facilitated for emotional compared to non-emotional faces. Sixty-eight participants matched angry, happy, and neutral face photographs either within a single visual field (i.e., within one hemisphere) or across opposite visual fields (i.e., between the two hemispheres). An overall performance advantage favoring across-field trials was modulated by the emotionality of the face. Specifically, the across-field advantage was significantly greater for angry and happy faces compared to neutral faces, a pattern evident for both accuracy and reaction time data. Possible interpretations of the enhanced interhemispheric processing advantage include increased computational complexity or subcortical transfer of emotionally salient information.