Real-time monitoring of mitochondrial oxygenation during machine perfusion using resonance Raman spectroscopy predicts organ function.

Organ transplantation is a life-saving procedure affecting over 100,000 people on the transplant waitlist. Ischemia reperfusion injury (IRI) is a major challenge in the field as it can cause post-transplantation complications and limit the use of organs from extended criteria donors. Machine perfusion technology has the potential to mitigate IRI; however, it currently fails to achieve its full potential due to a lack of highly sensitive and specific assays to assess organ quality during perfusion. We developed a real-time and non-invasive method of assessing organs during perfusion based on mitochondrial function and injury using resonance Raman spectroscopy. It uses a 441 nm laser and a high-resolution spectrometer to quantify the oxidation state of mitochondrial cytochromes during perfusion. This index of mitochondrial oxidation, or 3RMR, was used to understand differences in mitochondrial recovery of cold ischemic rodent livers during machine perfusion at normothermic temperatures with an acellular versus cellular perfusate. Measurement of the mitochondrial oxidation revealed that there was no difference in 3RMR of fresh livers as a function of normothermic perfusion when comparing acellular versus cellular-based perfusates. However, following 24 h of static cold storage, 3RMR returned to baseline faster with a cellular-based perfusate, yet 3RMR progressively increased during perfusion, indicating injury may develop over time. Thus, this study emphasizes the need for further refinement of a reoxygenation strategy during normothermic machine perfusion that considers cold ischemia durations, gradual recovery/rewarming, and risk of hemolysis.

Clinical and Genomic Predictors of Adverse Events in Newly Diagnosed Glioblastoma.

PURPOSE: Adverse clinical events cause significant morbidity in patients with GBM (GBM). We examined whether genomic alterations were associated with AE (AE) in patients with GBM. EXPERIMENTAL DESIGN: We identified adults with histologically confirmed IDH-wild-type GBM with targeted next-generation sequencing (OncoPanel) at Dana Farber Cancer Institute from 2013 to 2019. Seizure at presentation, lymphopenia, thromboembolic events, pseudoprogression, and early progression (within 6 months of diagnosis) were identified as AE. The biologic function of genetic variants was categorized as loss-of-function (LoF), no change in function, or gain-of-function (GoF) using a somatic tumor mutation knowledge base (OncoKB) and consensus protein function predictions. Associations between functional genomic alterations and AE were examined using univariate logistic regressions and multivariable regressions adjusted for additional clinical predictors. RESULTS: Our study included 470 patients diagnosed with GBM who met the study criteria. We focused on 105 genes that had sequencing data available for ≥ 90% of the patients and were altered in ≥10% of the cohort. Following false-discovery rate (FDR) correction and multivariable adjustment, the TP53, RB1, IGF1R, and DIS3 LoF alterations were associated with lower odds of seizures, while EGFR, SMARCA4, GNA11, BRD4, and TCF3 GoF and SETD2 LoF alterations were associated with higher odds of seizures. For all other AE of interest, no significant associations were found with genomic alterations following FDR correction. CONCLUSIONS: Genomic biomarkers based on functional variant analysis of a routine clinical panel may help identify AE in GBM, particularly seizures. Identifying these risk factors could improve the management of patients through better supportive care and consideration of prophylactic therapies.

Noninvasive treatment of cutaneous neurofibromas (cNFs): Results of a randomized prospective, direct comparison of four methods.

BACKGROUND: People with Neurofibromatosis Type 1 (NF1) suffer disfigurement and pain when hundreds to thousands of cutaneous neurofibromas (cNFs) appear and grow throughout life. Surgical removal of cNFs under anesthesia is the only standard therapy, leaving surgical scars. OBJECTIVE: Effective, minimally-invasive, safe, rapid, tolerable treatment(s) of small cNFs that may prevent tumor progression. METHODS: Safety, tolerability, and efficacy of 4 different treatments were compared in 309, 2-4 mm cNFs across 19 adults with Fitzpatrick skin types (FST) I-IV: radiofrequency (RF) needle coagulation, 755 nm alexandrite laser with suction, 980 nm diode laser, and intratumoral injection of 10 mg/mL deoxycholate. Regional pain, clinical responses, tumor height and volume (by 3D photography) were assessed before, 3 and 6 months post-treatment. Biopsies were obtained electively at 3 months. RESULTS: There was no scarring or adverse events > grade 2. Each modality significantly (P < .05) reduced or cleared cNFs, with large variation between tumors and participants. Alexandrite laser and deoxycholate were fast and least painful; 980 nm laser was most painful. Growth of cNFs was not stimulated by treatment(s) based on height and volume values at 3 and 6 months compared to baseline. LIMITATIONS: Intervention was a single treatment session; dosimetry has not been optimized. CONCLUSIONS: Small cNFs can be rapidly and safely treated without surgery.

Right-to-left ventricular ratio is higher in systole than diastole in patients with acute pulmonary embolism.

OBJECTIVES: In acute pulmonary embolism (PE), the right ventricle (RV) may dilate compromising left ventricular (LV) size, thereby increasing RV/LV ratio. End-diastolic RV/LV ratio is often used in PE risk stratification, though the cause of death is RV systolic failure. We aimed to confirm our pre-clinical observations of higher RV/LV ratio in systole compared to diastole in human patients with PE. METHODS: We blinded and independently analyzed echocardiograms from 606 patients with PE, evaluated by a Pulmonary Embolism Response Team. We measured RV/LV ratios in end-systole and end-diastole and fractional area change (FAC). Our primary outcome was a composite of 7-day clinical deterioration, treatment escalation or death. Secondary outcomes were 7-day and 30-day all-cause mortality. RESULTS: RV/LV ratio was higher in systole compared to diastole (median 1.010 [.812-1.256] vs. .975 [.843-1.149], p < .0001). RV/LV in systole and diastole were correlated (slope = 1.30 [95% CI 1.25-1.35], p < .0001 vs. slope = 1). RV/LV ratios in both systole and diastole were associated with the primary composite outcome but not with all-cause mortality. CONCLUSION: The RV/LV ratio is higher when measured in systole versus in diastole in patients with acute PE. The two approaches had similar associations with clinical outcomes, that is, it appears reasonable to measure RV/LV ratio in diastole.

Bavituximab Decreases Immunosuppressive Myeloid-Derived Suppressor Cells in Newly Diagnosed Glioblastoma Patients.

PURPOSE: We evaluated the efficacy of bavituximab-a mAb with anti-angiogenic and immunomodulatory properties-in newly diagnosed patients with glioblastoma (GBM) who also received radiotherapy and temozolomide. Perfusion MRI and myeloid-related gene transcription and inflammatory infiltrates in pre-and post-treatment tumor specimens were studied to evaluate on-target effects (NCT03139916). PATIENTS AND METHODS: Thirty-three adults with IDH--wild-type GBM received 6 weeks of concurrent chemoradiotherapy, followed by 6 cycles of temozolomide (C1-C6). Bavituximab was given weekly, starting week 1 of chemoradiotherapy, for at least 18 weeks. The primary endpoint was proportion of patients alive at 12 months (OS-12). The null hypothesis would be rejected if OS-12 was ≥72%. Relative cerebral blood flow (rCBF) and vascular permeability (Ktrans) were calculated from perfusion MRIs. Peripheral blood mononuclear cells and tumor tissue were analyzed pre-treatment and at disease progression using RNA transcriptomics and multispectral immunofluorescence for myeloid-derived suppressor cells (MDSC) and macrophages. RESULTS: The study met its primary endpoint with an OS-12 of 73% (95% confidence interval, 59%-90%). Decreased pre-C1 rCBF (HR, 4.63; P = 0.029) and increased pre-C1 Ktrans were associated with improved overall survival (HR, 0.09; P = 0.005). Pre-treatment overexpression of myeloid-related genes in tumor tissue was associated with longer survival. Post-treatment tumor specimens contained fewer immunosuppressive MDSCs (P = 0.01). CONCLUSIONS: Bavituximab has activity in newly diagnosed GBM and resulted in on-target depletion of intratumoral immunosuppressive MDSCs. Elevated pre-treatment expression of myeloid-related transcripts in GBM may predict response to bavituximab.

Prospective phase II trial of the dual mTORC1/2 inhibitor vistusertib for progressive or symptomatic meningiomas in persons with neurofibromatosis 2.

Background: Meningiomas occur in 80% of persons with neurofibromatosis 2 (NF2) and cause significant mortality and morbidity, yet there are no effective medical treatments. NF2-deficient tumors have constitutive activation of mammalian/mechanistic target of rapamycin (mTOR), and treatment with mTORC1 inhibitors results in growth arrest in a minority of tumors, with paradoxical activation of the mTORC2/AKT pathway. We studied the effect of vistusertib, a dual mTORC1/mTORC2 inhibitor, in NF2 patients with progressive or symptomatic meningiomas. Methods: Vistusertib was administered orally at 125 mg twice daily for 2 consecutive days each week. The primary endpoint was the imaging response in the target meningioma, defined as a volume decrease of 20% compared with the baseline. Secondary endpoints included toxicity, imaging response of nontarget tumors, quality of life, and genetic biomarkers. Results: Eighteen participants (13 female), median age of 41 (range, 18-61) years, were enrolled. In target meningiomas, the best response was partial response (PR) in 1/18 tumors (6%) and stable disease (SD) in 17/18 tumors (94%). For all measured intracranial meningiomas and vestibular schwannomas, the best imaging response was PR in 6/59 tumors (10%) and SD in 53 (90%). Treatment-related grade 3/4 adverse events occurred in 14 (78%) participants, and 9 participants discontinued treatment due to side effects. Conclusions: Although the study did not meet the primary endpoint, vistusertib treatment was associated with high rates of SD in progressive NF2-related tumors. However, this dosing regimen for vistusertib was poorly tolerated. Future studies of dual mTORC inhibitors for NF2 should focus on optimizing tolerability and evaluating the relevance of tumor stability in participants.

Translational Potential of Fluorescence Polarization for Breast Cancer Cytopathology.

Breast cancer is the most common malignancy in women. The standard of care for diagnosis involves invasive core needle biopsy followed by time-consuming histopathological evaluation. A rapid, accurate, and minimally invasive method to diagnose breast cancer would be invaluable. Therefore, this clinical study investigated the fluorescence polarization (Fpol) of the cytological stain methylene blue (MB) for the quantitative detection of breast cancer in fine needle aspiration (FNA) specimens. Cancerous, benign, and normal cells were aspirated from excess breast tissues immediately following surgery. The cells were stained in aqueous MB solution (0.05 mg/mL) and imaged using multimodal confocal microscopy. The system provided MB Fpol and fluorescence emission images of the cells. Results from optical imaging were compared to clinical histopathology. In total, we imaged and analyzed 3808 cells from 44 breast FNAs. Fpol images displayed quantitative contrast between cancerous and noncancerous cells, whereas fluorescence emission images showed the morphological features comparable to cytology. Statistical analysis demonstrated that MB Fpol is significantly higher (p < 0.0001) in malignant vs. benign/normal cells. It also revealed a correlation between MB Fpol values and tumor grade. The results indicate that MB Fpol could provide a reliable, quantitative diagnostic marker for breast cancer at the cellular level.

Patient-Reported Receipt of Oncology Clinician-Delivered Brief Tobacco Treatment (5As) Six Months following Cancer Diagnosis.

INTRODUCTION: Smoking after a cancer diagnosis represents a modifiable health risk. It is recommended that oncology clinicians address tobacco use among their patients using the 5As brief model: Asking about use, Advising users to quit, Assessing willingness to quit, Assisting in quit attempts (counseling and medication), and Arranging follow-up. However, cross-sectional studies have found limited adoption of 5As (especially Assist and Arrange) in oncology settings. Further investigation is needed to understand changes in, and factors associated with, 5As delivery over time. METHODS: Patients recently diagnosed with cancer and reporting current smoking (N = 303) enrolled in a smoking cessation clinical trial and completed three longitudinal surveys; at pre-intervention baseline and 3- and 6-month follow-up post-enrollment. Patient-level correlates of 5As receipt at baseline, 3 months, and 6 months were identified using multilevel regression models. RESULTS: At baseline, patient-reported rates of 5As receipt from oncology clinicians ranged from 85.17% (Ask) to 32.24% (Arrange). Delivery declined from baseline to 6-month follow-up for all 5As, with the largest declines observed for Ask, Advise, Assess, and Assist-Counseling. Diagnosis of a smoking-related cancer was associated with greater odds of 5As receipt at baseline but lower odds at 6-month follow-up. At each time point, female gender, religiosity, advanced disease, cancer-related stigma, and smoking abstinence were associated with lower odds of 5As receipt, while reporting a recent quit attempt prior to enrollment was associated with higher odds of 5As receipt. CONCLUSION: Oncology clinicians' 5As delivery declined over time. Clinician delivery of the 5As varied based on patients' sociodemographics, clinical and smoking characteristics, and psychosocial factors.

Co-Targeting IL-6 and EGFR signaling for the treatment of schwannomatosis and associated pain.

Patients with Schwannomatosis (SWN) overwhelmingly present with intractable, debilitating chronic pain. There are no effective therapies to treat SWN. The drivers of pain response and tumor progression in SWN are not clear. The pain is not proportionally linked to tumor size and is not always relieved by tumor resection, suggesting that mechanisms other than mechanical nerve compression exist to cause pain. SWN research is limited by the lack of clinically-relevant models. Here, we established novel patient-derived xenograft (PDX) models, dorsal root ganglia (DRG) imaging model, and combined with single-cell resolution intravital imaging and RNASeq, we discovered: i) schwannomas on the peripheral nerve cause macrophage influx into the DRG, via secreting HMGB1 to directly stimulate DRG neurons to express CCL2, the key macrophage chemokine, ii) once recruited, macrophages cause pain response via overproduction of IL-6, iii) IL-6 blockade in a therapeutic setting significantly reduces pain but has modest efficacy on tumor growth, iv) EGF signaling is a potential driver of schwannoma growth and escape mechanism from anti-IL6 treatment, and v) combined IL-6 and EGFR blockade simultaneously controlled pain and tumor growth in SWN models. Our findings prompted the initiation of phase II clinical trial ( NCT05684692 ) for pain relief in patients with SWN.

Patients With Serious Mental Illness Can Engage in Tobacco Treatment Trials and Tobacco Cessation Interventions During Cancer Treatment.

PURPOSE: More than half of individuals with serious mental illness (SMI) smoke, contributing to premature cancer mortality. A cancer diagnosis provides an opportunity to assist with smoking cessation; however, supportive oncology trials frequently exclude patients with SMI. To fill this gap, we examined differences in engagement and tobacco cessation in a pragmatic clinical trial. METHODS: We recruited 303 participants from two National Cancer Institute-designated Comprehensive Cancer Centers, of which 10% had prior diagnoses of SMI (major depressive disorder, bipolar disorder, and schizophrenia spectrum disorders). We compared self-reported smoking behaviors, patient attitudes and beliefs about cessation, and rates of trial completion, engagement, and smoking abstinence among recently diagnosed patients with cancer with and without SMI. Six months after trial completion, we completed qualitative interviews on barriers and facilitators to tobacco cessation in a random sample of participants with SMI. RESULTS: Trial participants with SMI had similar motivation to quit smoking as those without SMI. Additionally, participants with SMI had a similar ability to engage in a tobacco treatment trial (6.5 counseling sessions completed v 7.3 sessions) and benefit from tobacco treatment as those without SMI (32.3% v 27.8% 6-month quit rates). CONCLUSION: Patients with cancer and SMI were able to engage in and benefit from a tobacco cessation trial integrated into cancer care. A cancer diagnosis provides an opportunity to assist patients with SMI with smoking cessation referrals and treatment. Pragmatic supportive oncology trials that include a diverse population of adults with SMI are needed to inform care delivery and improve cancer outcomes for patients with SMI and cancer.

Ten-Year Follow-up of Internal Neurofibroma Growth Behavior in Adult Patients With Neurofibromatosis Type 1 Using Whole-Body MRI.

BACKGROUND AND OBJECTIVES: Internal neurofibromas, including plexiform neurofibromas (PNF), can cause significant morbidity in patients with neurofibromatosis type 1 (NF1). PNF growth is most pronounced in children and young adults, with more rapid growth thought to occur in a subset of PNF termed distinct nodular lesions (DNL). Growth behavior of internal neurofibromas and DNL in older adults is not well documented; yet knowledge thereof is important for patient risk stratification and clinical trial design. The primary objective of this study was to evaluate the long-term growth behavior of internal neurofibromas in adults with NF1. Secondary objectives were to correlate tumor growth behavior with patient-specific, tumor-specific, and patient-reported variables. METHODS: In this prospective cohort study, internal neurofibromas were identified on coronal short TI inversion recovery sequences on baseline and follow-up whole-body MRIs (WBMRIs). Tumor growth and shrinkage were defined as a volume change ≥20%. The association between tumor growth and patient-specific (baseline age, sex, and genotype), tumor-specific (morphology, location, DNL presence on baseline WBMRI, and maximum standardized uptake value on baseline PET imaging), and patient-reported variables (endogenous and exogenous hormone exposure, pain intensity, and quality of life) was assessed using the Spearman correlation coefficient and Kruskal-Wallis test. RESULTS: Of 106 patients with a baseline WBMRI obtained as part of a previous research study, 44 had a follow-up WBMRI. Three additional patients with WBMRIs acquired for clinical care were included, generating 47 adults for this study. The median age during baseline WBMRI was 42 years (range 18-70). The median time between WBMRIs was 10.4 years. Among 324 internal neurofibromas, 62.8% (56% of PNF and 62.1% of DNL) shrank spontaneously without treatment and 17.1% (17.9% of PNF and 13.8% of DNL) grew. Growth patterns were heterogeneous within participants. Patient-specific, tumor-specific, and patient-reported variables (including endogenous and exogenous hormone exposure) were not strong predictors of tumor growth. DISCUSSION: Internal neurofibroma growth behavior in older adults differs fundamentally from that in children and young adults, with most tumors, including DNL, demonstrating spontaneous shrinkage. Better growth models are needed to understand factors that influence tumor growth. These results will inform clinical trial design for internal neurofibromas.

Clinicopathologic Characteristics and Outcomes for Patients With KRAS G12D-Mutant NSCLC.

Introduction: Co-occurring mutations in KRAS-mutant NSCLC are associated with discrete biological properties and modulate therapeutic susceptibilities. As G12D-specific inhibitors are expected to enter the clinic, we sought to investigate the characteristics and outcomes of patients with KRAS G12D-mutant NSCLC. Methods: This was a retrospective single-institution study. Patients with NSCLC and KRAS G12D mutations detected by the Massachusetts General Hospital SNaPshot next-generation sequencing assay were identified. Clinical and pathologic characteristics were collected by chart review. Results: A total of 107 patients with KRAS G12D-mutant NSCLC were identified. Most patients were former smokers (80, 74.8%) and had tumors with adenocarcinoma pathologic subtype (93, 86.9%). Among 56 patients evaluated for programmed death-ligand 1 expression, tumor proportion score was less than 50% in 43 (76.8%). Concomitant mutations were identified in STK11 (17 of 107, 15.9%), KEAP1 (10 of 58, 17.2%), TP53 (36 of 107, 33.6%), and SMARCA4 (11 of 107, 10.3%). Among 57 patients treated with first-line therapy, patients with STK11 co-mutations had shorter progression-free survival (1.2 mo, 95% confidence interval [CI]: 0.6-2.9 versus 4.1 mo, 95% CI: 2.5-6.0, p = 0.0235) and overall survival (4.3 mo, 95% CI: 1.2-10.6 versus 17.9 mo, 95% CI: 8.6-31.1, p = 0.0018) compared with wild type. Patients with KEAP1 co-mutations had shorter overall survival (4.6 mo, 95% CI: 1.2-10.6 versus 17.9 mo, 95% CI: 7.1-30.1, p = 0.0125) than those without. TP53 co-mutations exerted no influence on survival. Conclusions: Co-occurring mutations were common in patients with KRAS G12D-mutant NSCLC. STK11 and KEAP1 co-mutations were associated with worse clinical outcomes, whereas co-occurring TP53 did not affect survival.

Design of a randomized, placebo-controlled, phase 2 study evaluating the safety and efficacy of tanezumab for treatment of schwannomatosis-related pain.

BACKGROUND: Schwannomatosis (SWN) is a rare tumor suppressor syndrome that predisposes affected individuals to develop multiple schwannomas and, less often, meningiomas. The most common symptom is chronic, severe pain. No medications are broadly effective in treating SWN-associated pain. The clinical trial described in this manuscript is a phase 2, randomized, double-blind, placebo-controlled study investigating the safety and efficacy of tanezumab - a humanized monoclonal antibody that inhibits nerve growth factor - for treatment of SWN-related pain. As the first therapeutic trial for SWN-related pain, it also aims to evaluate trial endpoints, understand recruitment patterns, and improve clinical trial design in this rare disease. AIMS: The primary objective of this trial is to assess the analgesic efficacy of subcutaneous tanezumab 10 mg in subjects with SWN who continue pre-existing pain therapy (excluding non-steroidal anti-inflammatory drugs). The secondary objective is to assess safety in this population. Exploratory objectives include assessment of pain features, quality of life, and predictive biomarkers. METHODS: The study is comprised of four periods (pre-treatment, double-blind treatment, single-arm treatment, safety follow-up) across 10 months with a delayed-start trial design to allow all participants to receive tanezumab. Forty-six participants will be enrolled and randomized 1:1 to receive either tanezumab or placebo subcutaneously in the double-blind treatment period; all participants receive tanezumab during the single-arm treatment period. CONCLUSIONS: This study is the first therapeutic trial for SWN patients and targets a biological driver of SWN-related pain. It aims to establish a model for future pain studies in SWN and other rare diseases. CLINICAL TRIAL REGISTRATION: NCT04163419 on ClinicalTrials.gov.

Study protocol for a hybrid type 1 effectiveness-implementation trial testing virtual tobacco treatment in oncology practices [Smokefree Support Study 2.0].

BACKGROUND: Persistent smoking among patients diagnosed with cancer is associated with adverse clinical outcomes, yet an evidence-based tobacco use intervention has not been well-integrated into cancer care in community oncology settings. This paper describes the protocol of a nation-wide clinical trial conducted by the ECOG-ACRIN National Cancer Institute (NCI) Community Oncology Research Program (NCORP) Research Base to assess the effectiveness of a virtual tobacco treatment intervention and the process of implementing tobacco treatment in NCORP community oncology settings. METHODS/DESIGN: This two-arm, multisite (n: 49 NCORP sites) hybrid type 1 effectiveness-implementation randomized controlled trial compares the effectiveness of a Virtual Intervention Treatment (VIT) versus an Enhanced Usual Control (EUC) among English and Spanish speaking patients recently diagnosed with cancer, reporting current smoking and receiving care at a participating NCORP Community or Minority/Underserved Site. The VIT includes up to 11 virtual counseling sessions with a tobacco treatment specialist and up to 12 weeks of nicotine replacement therapy (NRT). The EUC arm receives a referral to the NCI Quitline. The primary study outcome is biochemically confirmed 7-day point prevalence smoking abstinence. Moderators of treatment effect will be assessed. The study evaluates implementation processes from participating NCORP site staff via survey, administrative, and focus group data, including reach, acceptability, appropriateness, fidelity, feasibility, adoption, cost and sustainability outcomes. DISCUSSION: This trial will generate findings about the effectiveness of an evidence-based virtual tobacco treatment intervention targeting patients diagnosed with cancer and illuminate barriers and facilitators that influence implementing tobacco treatment into community oncology settings nationally. In the era of COVID-19, virtual care solutions are vital for maximizing access and utilization of tobacco treatment delivery. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03808818) on January 18th, 2019; Last update posted: May 21st, 2020.

A Phase 2 Study of Lorlatinib in Patients With ROS1-Rearranged Lung Cancer With Brain-Only Progression on Crizotinib.

Introduction: The central nervous system (CNS) is a common site of progression among patients with ROS1-rearranged lung cancer receiving crizotinib. We conducted a phase 2 study to evaluate the intracranial efficacy of lorlatinib in patients with ROS1-rearranged lung cancer who developed CNS-only progression on crizotinib. Methods: Patients with metastatic ROS1-rearranged lung cancer with CNS-only progression on crizotinib received lorlatinib 100 mg daily. The primary end point was intracranial disease control rate at 12 weeks per modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included intracranial and extracranial progression-free survival, intracranial objective response rate, and safety/tolerability. Results: A total of 16 patients were enrolled between November 2016 and January 2019. Nine patients (56%) had received prior CNS radiation, with a median of 10.9 months between radiation and lorlatinib. At 12 weeks, the intracranial disease control rate was 100% and intracranial objective response rate was 87%. While on study, the complee intracranial response rate was 60%. With median follow-up of 22 months, seven patients experienced disease progression, including five patients with CNS relapse. The median intracranial and extracranial progression-free survivals were 38.8 months (95% confidence interval: 16.9-not reported) and 41.1 months (95% confidence interval: 17.6-not reported), respectively. Molecular analysis of plasma or tissue from patients with extracranial progression on lorlatinib revealed ROS1 G2032R (n = 1), ROS1 L2086F (n = 1), and CCDC6-RET fusion plus ROS1 G2032R (n = 1). The safety profile of lorlatinib was consistent with prior studies. There were 11 patients (69%) who required dose reduction, including one patient who discontinued treatment for grade 3 edema. No grade greater than or equal to 4 adverse events were observed. Conclusions: Lorlatinib induced durable intracranial responses in patients with ROS1-rearranged NSCLC and prior isolated CNS progression on crizotinib.

Cost-effectiveness of Implementing Smoking Cessation Interventions for Patients With Cancer.

Importance: Guidelines recommend cancer care clinicians offer smoking cessation treatment. Cost analyses will help stakeholders understand and plan for implementation of cessation programs. Objective: To estimate the incremental cost per quit (ICQ) of adopting an intensive smoking cessation intervention among patients undergoing treatment at cancer care clinics, from a clinic perspective. Design, Setting, and Participants: This economic evaluation, a secondary analysis of the Smokefree Support Study (conducted 2013-2018; completed 2021), used microcosting methods and sensitivity analyses to estimate the ICQ of the interventions. Participants included patients undergoing treatment for a broad range of solid tumors and lymphomas who reported current smoking and were receiving care at cancer care clinics within 2 academic medical centers. Exposures: Intensive smoking cessation treatment (up to 11 counseling sessions with free medications), standard of care (up to 4 counseling sessions with medication advice), or usual care (referral to the state quitline). Main Outcomes and Measures: Total costs, component-specific costs, and the ICQ of the intensive smoking cessation treatment relative to both standard of care (comparator in the parent randomized trial) and usual care (a common comparator outside this trial) were calculated. Overall and post hoc site-specific estimates are provided. Because usual care was not included in the parent trial, sensitivity analyses were conducted to assess how assumptions about usual care quit rates affected study outcomes (ie, base case [from a published smoking cessation trial among patients with thoracic cancer], best case, and conservative case scenarios). Results: The per-patient costs of offering intensive smoking cessation treatment, standard of care, and usual care were $1989, $1482, and $0, respectively. For intensive treatment, the dominant costs were treatment (35%), staff supervision (26%), and patient enrollment (24%). Relative to standard of care, intensive treatment had an overall ICQ of $3906, and one site had an ICQ of $2892. Relative to usual care, intensive treatment had an ICQ of $9866 overall (base case), although at one site, the ICQ was $5408 (base case) and $3786 (best case). Conclusions and Relevance: In this economic evaluation study, implementation of an intensive smoking cessation treatment intervention was moderately to highly cost-effective, depending on existing smoking cessation services in place.

Phase II Study of Cabozantinib in Patients With Bone Metastasis.

Bone metastases are often difficult to manage as they can be symptomatic and skeletal-related events (SREs) can contribute to significant morbidity and declines in performance status. We sought to identify a novel medical treatment for bone metastasis by testing the safety and efficacy of cabozantinib in patients with bone metastasis arising from non-breast, non-prostate, malignant solid tumors. Patients were administered cabozantinib as an oral drug starting at 60 mg per day and radiologic measurements were performed at baseline and every 8 weeks. Thirty-seven patients were enrolled. No SREs were observed throughout the study. Twenty patients had disease measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Four of 20 had a partial response by RECIST. An additional 12 patients had some decrease in tumor burden with nine of these having a decrease in tumor burden of at least 10% by RECIST. Six of the patients with at least a minor response had sarcoma. Sixteen patients had biomarkers of bone turnover measured before and after treatment. Most of these patients demonstrated decrease in urine and serum N-telopeptide and serum C-telopeptide. However, these changes in biomarkers of bone turnover did not correlate with radiographic changes measured by RECIST. This study demonstrates clinical activity and safety for cabozantinib in heavily pretreated patients with bone metastasis and shows activity for cabozantinib in patients with metastatic sarcoma.

High-Dose Osimertinib for CNS Progression in EGFR+ NSCLC: A Multi-Institutional Experience.

Introduction: This multicenter review evaluated the efficacy and safety of osimertinib dose escalation for central nervous system (CNS) progression developing on osimertinib 80 mg in EGFR-mutant NSCLC. Methods: Retrospective review identified 105 patients from eight institutions with advanced EGFR-mutant NSCLC treated with osimertinib 160 mg daily between October 2013 and January 2020. Radiographic responses were clinically assessed, and Kaplan-Meier analyses were used. We defined CNS disease control as the interval from osimertinib 160 mg initiation to CNS progression or discontinuation of osimertinib 160 mg. Results: Among 105 patients treated with osimertinib 160 mg, 69 were escalated for CNS progression, including 24 treated with dose escalation alone (cohort A), 34 who received dose-escalated osimertinib plus concurrent chemotherapy and/or radiation (cohort B), and 11 who received osimertinib 160 mg without any prior 80 mg exposure. The median duration of CNS control was 3.8 months (95% confidence interval [CI], 1.7-5.8) in cohort A, 5.1 months (95% CI, 3.1-6.5) in cohort B, and 4.2 months (95% CI 1.6-not reached) in cohort C. Across all cohorts, the median duration of CNS control was 6.0 months (95% CI, 5.1-9.0) in isolated leptomeningeal progression (n = 27) and 3.3 months (95% CI, 1.0-3.1) among those with parenchymal-only metastases (n = 23). Patients on osimertinib 160 mg experienced no severe or unexpected side effects. Conclusion: Among patients with EGFR-mutant NSCLC experiencing CNS progression on osimertinib 80 mg daily, dose escalation to 160 mg provided modest benefit with CNS control lasting approximately 3 to 6 months and seemed more effective in patients with isolated leptomeningeal CNS progression.

Phase II Study of Lorlatinib in Patients With Anaplastic Lymphoma Kinase-Positive Lung Cancer and CNS-Specific Relapse.

PURPOSE: The CNS is a recurrent site of progression in anaplastic lymphoma kinase (ALK)-rearranged (ALK+) lung cancer. Lorlatinib is a third-generation ALK inhibitor developed to penetrate the CNS and overcome ALK resistance mutations. We conducted a phase II study to evaluate the intracranial activity of lorlatinib in patients with CNS-only progression on second-generation ALK inhibitors. METHODS: Patients with ALK+ lung cancer who had intracranial progression on ≥ 1 ALK inhibitor without measurable extracranial disease received lorlatinib 100 mg once daily. The primary end point was intracranial disease control rate at 12 weeks per modified RECIST v1.1. Secondary end points included intracranial progression-free survival, intracranial objective response rate, and safety/tolerability. RESULTS: Twenty-three patients were enrolled between November 2016 and January 2019. Fifteen (65%) patients had irradiated CNS metastases, with a median of 20.2 months between radiation and lorlatinib. Control of intracranial disease was observed in 21 (95%) evaluable patients at 12 weeks. The intracranial objective response rate was 59% with six complete and seven partial responses. The median intracranial progression-free survival was 24.6 months (95% CI, 20.2 to not reached). With a median follow-up of 16.8 months, nine patients developed disease progression, including four patients with CNS progression. The most common treatment-related adverse events were hypercholesterolemia (96%), hypertriglyceridemia (87%), edema (65%), cognitive effects (52%), and mood effects (43%). Three patients discontinued treatment because of toxicity, including two patients with fatal respiratory events. CONCLUSION: Lorlatinib induced durable intracranial disease control in patients with CNS-only relapse on second-generation ALK inhibitors, suggesting that tumors with CNS-limited progression on brain-penetrant ALK tyrosine kinase inhibitors remain ALK-dependent.

Fluorescence Polarization Imaging of Methylene Blue Facilitates Quantitative Detection of Thyroid Cancer in Single Cells.

BACKGROUND: Diagnostic accuracy of the standard of care fine-needle aspiration cytology (FNAC) remains a significant problem in thyroid oncology. Therefore, a robust and accurate method for reducing uncertainty of cytopathological evaluation would be invaluable. METHODS: In this double-blind study, we employed fluorescence emission and quantitative fluorescence polarization (Fpol) confocal imaging for sorting thyroid cells into benign/malignant categories. Samples were collected from malignant tumors, benign nodules, and normal thyroid epithelial tissues. RESULTS: A total of 32 samples, including 12 from cytologically indeterminate categories, were stained using aqueous methylene blue (MB) solution, imaged, and analyzed. Fluorescence emission images yielded diagnostically relevant information on cytomorphology. Significantly higher MB Fpol was measured in thyroid cancer as compared to benign and normal cells. The results obtained from 12 indeterminate samples revealed that MB Fpol accurately differentiated benign and malignant thyroid nodules. CONCLUSIONS: The developed imaging approach holds the potential to provide an accurate and objective biomarker for thyroid cancer, improve diagnostic accuracy of cytopathology, and decrease the number of lobectomy and near-total thyroidectomy procedures.