Pain Reduction of Ibuprofen Sodium Dihydrate Alone and in Combination with Acetaminophen in an Untreated Endodontic Pain Model: A Randomized, Double-blind Investigation.

INTRODUCTION: Most pain studies have been based on a post-surgical, third molar model using ibuprofen (IBU)/acetaminophen (APAP). Studies have found quicker onset of pain relief with a newer formulation of IBU - ibuprofen sodium dihydrate (ISD). The purpose of this study was to compare pain reduction of ISD/APAP to ISD in an acute endodontic pain model of untreated patients experiencing moderate to severe pain with symptomatic apical periodontitis. METHODS AND MATERIALS: In this double-blind randomized study, 64 adult emergency patients in acute moderate to severe pain, a pulpal diagnosis of symptomatic irreversible pulpitis or necrosis, and symptomatic apical periodontitis participated. Each patient randomly received either one dose of 768 mg ISD/1000 mg APAP or one dose 768 mg ISD. Pain intensity scores were recorded every 15 minutes over 240 minutes using the Heft-Parker VAS along with time to first sign of pain relief, time to meaningful pain relief, and time to 50% pain relief also recorded. The data were analyzed statistically. RESULTS: Both ISD and ISD/APAP groups showed a progressive decrease in pain from baseline to 120 minutes after medication administration. Afterwards, a relative plateau was seen in the patients' pain. There was no difference in the VAS scores between the ISD and ISD/APAP at any given time point, time to first sign of pain relief, time to meaningful pain relief, and time to 50% pain relief. CONCLUSIONS: The addition of APAP to ISD for pain control in an untreated endodontic pain model did not differ significantly from ISD alone.

Effect of analysis software program on measured deviations in complete arch, implant-supported framework scans.

STATEMENT OF PROBLEM: Implementation of fabrication trueness analysis by using a recently introduced nonmetrology-grade freeware program may help clinicians and dental laboratory technicians in their routine practice. However, knowledge of the performance of this freeware program when compared with the International Organization for Standardization recommended metrology-grade analysis software program is limited. PURPOSE: The purpose of this in vitro study was to evaluate the effect of an analysis software program on measured deviations in the complete arch, implant-supported framework scans. MATERIAL AND METHODS: A total of 20 complete arch, implant-supported frameworks were fabricated from a master standard tessellation language (STL) file from either polyetheretherketone (PEEK) or titanium (Ti) (n=10). All frameworks were then digitized by using different scanners to generate test STLs. All STL files were imported into a nonmetrology-grade freeware program (Medit Link) and a metrology-grade software program (Geomagic Control X) to measure the overall and marginal deviations of frameworks from the master STL file by using the root mean square (RMS) method. Data were analyzed by using the two 1-sided paired t test procedure, in which 50 µm was considered as the minimal clinically meaningful difference (α=.05). RESULTS: When overall RMS values were considered, the nonmetrology-grade freeware program was not inferior to the metrology-grade software program (P<.05). When marginal RMS values were considered, the nonmetrology-grade freeware program was inferior to the metrology-grade software program only when PEEK frameworks were scanned with an E4 laboratory scanner (P>.05). CONCLUSIONS: The use of the tested nonmetrology-grade freeware program resulted in overall deviation measurements similar to those when a metrology-grade software program was used. The freeware program was inferior when marginal deviations were analyzed on E4 scans of a PEEK framework, which was the only scanner-material pair that led to a significant difference, among the 15 pairs tested.

Patient-centered dosing: oncologists' perspectives about treatment-related side effects and individualized dosing for patients with metastatic breast cancer (MBC).

PURPOSE: Although metastatic breast cancer (MBC) is treatable, it is not curable and most patients remain on treatment indefinitely. While oncologists commonly prescribe the recommended starting dose (RSD) from the FDA-approved label, patient tolerance may differ from that seen in clinical trials. We report on a survey of medical oncologists' perspectives about treatment-related toxicity and willingness to discuss flexible dosing with patients. METHODS: We disseminated a confidential survey via social media/email in Spring 2021. Eligible respondents needed to be US-based medical oncologists with experience treating patients with MBC. RESULTS: Of 131 responses, 119 were eligible. Physicians estimated that 47% of their patients reported distressing treatment-related side effects; of these, 15% visited the Emergency Room/hospital and 37% missed treatment. 74% (n = 87) of doctors reported improvement of patient symptoms after dose reduction. 87% (n = 104) indicated that they had ever, if appropriate, initiated treatment at lower doses. Most (85%, n = 101) respondents did not believe that the RSD is always more effective than a lower dose and 97% (n = 115) were willing to discuss individualized dosing with patients. CONCLUSION: Treatment-related side effects are prevalent among patients with MBC, resulting in missed treatments and acute care visits. To help patients tolerate treatment, oncologists may decrease initial and/or subsequent doses. The majority of oncologists reject the premise that a higher dose is always superior and are willing to discuss individualized dosing with patients. Given potential improvements regarding quality of life and clinical care, dose modifications should be part of routine shared decision-making between patients and oncologists.

The impact of anti-CD20-based therapy on hypogammaglobulinemia in patients with follicular lymphoma.

Although treatment with anti-CD20 monoclonal antibodies (mAb) has improved outcomes in B-cell malignancies, it's associated with increased risk of hypogammaglobulinemia (HG). Our study aimed to determine the effects of anti-CD20 mAb on serum immunoglobulins (Ig) in follicular lymphoma (FL). Ig concentrations, infectious complications, and need for intravenous Ig were evaluated by level of exposure to anti-CD20 mAb in 380 patients. Prevalence of HG significantly differed by level of treatment exposure (p < 0.001). Single course anti-CD20 mAb was associated with rising IgG (+10.3 mg/dL/year), whereas the addition of maintenance therapy (-7.4 mg/dL/year) or multiple courses of treatment (-10.3 mg/dL/year) was associated with declining IgG. Among patients treated with anti-CD20 mAb, 45.2% developed IgG-HG and 10.3% developed symptomatic IgG-HG. Pretreatment IgG levels gradually declined in all patients, suggesting tumor burden may contribute to HG. Baseline and periodic monitoring of serum Ig is appropriate in patients with FL, including those managed with active surveillance.

Phase 1 Clinical Trial of Trametinib and Ponatinib in Patients With NSCLC Harboring KRAS Mutations.

INTRODUCTION: Somatic KRAS mutations occur in 25% of patients with NSCLC. Treatment with MEK inhibitor monotherapy has not been successful in clinical trials to date. Compensatory activation of FGFR1 was identified as a mechanism of trametinib resistance in KRAS-mutant NSCLC, and combination therapy with trametinib and ponatinib was synergistic in in vitro and in vivo models. This study sought to evaluate this drug combination in patients with KRAS-mutant NSCLC. METHODS: A phase 1 dose escalation study of trametinib and ponatinib was conducted in patients with advanced NSCLC with KRAS mutations. A standard 3-plus-3 dose escalation was done. Patients were treated with the study therapy until intolerable toxicity or disease progression. RESULTS: A total of 12 patients with KRAS-mutant NSCLC were treated (seven at trametinib 2 mg and ponatinib 15 mg, five at trametinib 2 mg and ponatinib 30 mg). Common toxicities observed were rash, diarrhea, and fever. Serious adverse events potentially related to therapy were reported in five patients, including one death in the study and four cardiovascular events. Serious events were observed at both dose levels. Of note, 75% (9 of 12) were assessable for radiographic response and no confirmed partial responses were observed. The median time on study was 43 days. CONCLUSIONS: In this phase 1 study, in patients with KRAS-mutant advanced NSCLC, combined treatment with trametinib and ponatinib was associated with cardiovascular and bleeding toxicities. Exploring the combination of MEK and FGFR1 inhibition in future studies is potentially warranted but alternative agents should be considered to improve safety and tolerability.

Referral rate for obstructive sleep apnea in a pre-doctoral dental clinic using the STOP-Bang Questionnaire.

OBJECTIVES: Obstructive sleep apnea (OSA) is a common condition that can result in significant illness when untreated. Only 10%-20% of individuals with OSA are believed to be properly diagnosed. Consequently, dentists are encouraged to identify patients at high risk for OSA. The aim of this study was to determine whether patients in a dental school student clinic were referred for evaluation of OSA when appropriate. MATERIALS AND METHODS: All patients 18 or older admitted to the College of Dentistry between July 2017 and March 2020 completed a medical history form. Data were extracted from their responses to determine a STOP-Bang score, as well as data regarding a previous diagnosis of OSA and a list of referrals. Students are expected to refer patients appropriately where there are indications of a high risk of undiagnosed disease. In the case of a sleep apnea evaluation, this would include any patient whose STOP-Bang score was 5 or greater, per the lecture on sleep disorders. For patients identified as high risk, notes and referral forms were reviewed to determine if the appropriate referral occurred. RESULTS: Of the 21,312 new patients, 1098 (5.2%) were identified as high-risk for OSA. Of those, 398 (36%) had not been previously diagnosed with OSA. None of these 398 patients received a referral for further evaluation of OSA. CONCLUSION: The rate of referral for further evaluation for patients deemed at high risk for OSA was inadequate. Continued education and changes to the electronic health record are needed to ensure those at high-risk for OSA are appropriately managed.

Comparison of clinical outcomes between Invisalign and conventional fixed appliance therapies in adult patients with severe deep overbite treated with nonextraction.

INTRODUCTION: The use of aligner therapy for orthodontic treatment has increased substantially in the past decade. However, no study has compared treatment outcomes between the conventional fixed appliance and Invisalign therapies in patients with a severe deep overbite. METHODS: This study included 50 consecutive adult patients who underwent treatment with either Invisalign (n = 25; mean age, 23.3 ± 8.5 years) or a conventional fixed appliance (n = 25; mean age, 23.1 ± 6.5 years) to correct overbite >5 mm and >60% deep overbite. Cephalometric analysis and peer assessment rating was used to compare the clinical outcome between groups. RESULTS: Cephalometric analysis showed significant differences in N-Me (P = 0.0005) and Mp-L6 (P = 0.0001) between Invisalign and fixed appliance treatment groups. No significant differences were observed in the peer assessment rating analysis or total treatment duration between the 2 groups. CONCLUSIONS: Both Invisalign and conventional fixed appliances were effective in treating patients with a severe deep overbite. Invisalign therapy may be preferable over conventional fixed appliance therapy in patients with high angle and deep overbite. However, because this study had a retrospective design, the results should be viewed with caution.

Rehearsal's effect on long-term recall and comprehension of orthodontic informed consent.

INTRODUCTION: The purpose of this study was to determine if written rehearsal of informed consent improved 6-month recall and comprehension compared with the current best practices. METHODS: A consultation was provided and subjects read the modified informed consent document. They were randomized to group A (received the core and up to 4 custom elements of treatment, wrote what each image displayed) or group B (presentation of the 18 elements with core elements chunked at the end followed by up to 4 custom elements). Interviews recording knowledge recall/comprehension occurred immediately and after months later. RESULTS: Overall, no significant differences in baseline or 6-month follow-up scores were found between groups. Initially, group A outperformed group B in some core domains. There were no significant differences between groups in the change of scores from initial to follow-up. Follow-up scores were significantly lower than baseline scores (P <0.05). Higher initial scores were associated with larger drops at follow-up. A decrease in knowledge >20% was common. CONCLUSIONS: Overall the methods are comparable at baseline and 6-months. Initial content retention was roughly 60+%, with 6%-9% deterioration. For areas of treatment methods, risk, discomfort, and resorption at 6-months, the current processes failed the patient and left the practitioner vulnerable to risk management issues. Results support the rehearsal method with immediate feedback for misunderstandings as the preferred method for informed consent.

Comparison of 2 Invisalign tray generations using the Peer Assessment Rating index.

INTRODUCTION: This study aimed to establish if there is a significant difference in effectiveness between 2 generations of Invisalign trays in terms of Peer Assessment Rating (PAR) score reduction for finished patients from a graduate orthodontic clinic. METHODS: Forty-five pretreatment and posttreatment patients treated with the previous Invisalign material and 49 pretreatment and posttreatment patients treated with SmartTrack material were scored using the Peer Assessment Rating (PAR) index. Both groups were controlled for initial weighted PAR score, age, gender, and treatment time. The 2 generations were compared in regard to absolute reduction, percent reduction, and great improvement in PAR score. RESULTS: The mean absolute reduction in weighted PAR score between the groups was not statistically significant (P = 0.526). The mean percent reduction in weighted PAR score between the groups was not statistically significant (P = 0.210). The proportion of great improvement between the groups was not significant (P = 0.526). Only 6 of the 8 components of occlusion had enough variation to be modeled. An absolute reduction in unweighted PAR score was not significantly different between the groups for maxillary anterior alignment, overjet, or mandibular anterior alignment (P = 0.996, 1.000, and 0.114, respectively). Percent reduction in unweighted PAR score was not significantly different between the 2 groups for an anteroposterior, overbite, or transverse (P = 1.000, 1.000, and 1.000, respectively) relationships. CONCLUSIONS: Our study indicates that both generations of Invisalign aligners improved the malocclusion to a similar degree according to the PAR index. Patient-centric benefits of SmartTrack aligner should also be considered by the provider.

Time from diagnosis to 2nd treatment is a promising surrogate for overall survival in patients with advanced stage follicular lymphoma.

It is difficult to demonstrate an overall survival (OS) benefit in trials of immediate therapy vs observation in follicular lymphoma (FL). Time to 2nd treatment (TT2T) may be a preferred endpoint. We identified 584 consecutive patients at our institution with advanced stage FL grade 1-3 A for whom intention was observation (n = 248) or therapy (n = 338). Median time to 1st treatment (TT1T), TT2T, and OS were estimated (subdistribution function). Modified Kendall's tau (mKτ) was used to assess correlation between survival endpoints. Among initially observed patients, median TT1T was 3.3 years, TT2T was 12.1 years, 10-year treatment-free survival was 23%, and 10-year OS was 82%. TT2T was strongly correlated with OS following initial observation (mKτ 0.46, p = .004) or therapy (mKτ 0.53, p < .0001), while duration of observation was not. TT2T is a potential surrogate for OS. Given the outstanding survival in this population, early intervention trials should focus on identifying high risk patients.

Risk of breast implant associated anaplastic large cell lymphoma (BIA-ALCL) in a cohort of 3546 women prospectively followed long term after reconstruction with textured breast implants.

BACKGROUND: The risk of BIA-ALCL for patients with textured breast implants has been estimated between 1/2832 and 1/30,000 women. Existing studies estimating the numbers exposed and at risk, may have under reported cases, and/or lacked comprehensive follow-up. Our objective is to determine the risk of BIA-ALCL in a defined cohort of patients reconstructed with macro-textured breast implants and consistently followed long-term. METHODS: A prospective cohort study was conducted in patients who underwent breast reconstruction by a single surgeon at Memorial Sloan Kettering Cancer Center (MSKCC) from December 1992 to December 2017. Major events related to implants were prospectively recorded. We identified cases of BIA-ALCL by cross-checking clinical, pathology and external records data. Patients were followed until lymphoma occurrence or last follow-up. The primary outcomes were incidence rate per person-years and cumulative incidence. RESULTS: From 1992 to 2017, 3546 patients underwent 6023 breast reconstructions, mainly after breast cancer removal, or contralateral prophylactic mastectomy, using macro-textured surface expanders and implants. All reconstructions were performed by a single surgeon (PGC). Median follow-up was 8.1 years (range, 3 months - 30.9 years). Ten women, 1/354, developed ALCL after a median exposure of 11.5 years (range, 7.4-15.8 years). Overall risk of BIA-ALCL in our cohort is 1/355 women or 0.311 cases per 1000 person-years (95% CI 0.118 to 0.503). DISCUSSION: This study, the first to evaluate the risk of macro-textured breast implants from a prospective database with long term follow-up, demonstrates that the incidence rate of BIA-ALCL may be higher than previously reported. These results can help inform implant choice for women undergoing breast reconstruction.

Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations.

INTRODUCTION: Inherited mutations are easily detected factors that influence the disease courses and optimal treatment strategies of some cancers. Germline mutations in BRCA1 associated protein 1 (BAP1) are associated with unique disease profiles in mesothelioma, atypical spitz nevi, and uveal melanoma, but the patient characteristics of an unselected population of BAP1 carriers identified by an ascertainment prevalence study are unknown. METHODS: We collected blood samples, cancer histories, and occupational exposures from 183 unselected patients with BAP1-related diseases. Clinical information for each patient was obtained from medical records. Germline DNA was extracted from blood samples and sequenced using a next-generation sequencing assay. We tested screening criteria developed to identify patients with a possible germline BAP1 mutation. RESULTS: Pathogenic or likely pathogenic germline BAP1 mutations were observed in 5 of 180 sequenced specimens and were exclusively found in patients identified by our screening criteria. Several patients with characteristics suspicious for a heritable deleterious mutation did not have a germline BAP1 mutation. The prevalence of pathogenic germline BAP1 mutations in patients with mesothelioma was 4.4% (95% confidence interval 1.1-11.1). CONCLUSIONS: Results from the first unselected prevalence ascertainment study of germline BAP1 alterations suggest that the frequency of this mutation is low among patients with mesothelioma. The proposed screening criteria successfully identified all patients with germline BAP1-mutant mesothelioma. These screening guidelines may assist physicians in selecting patients who would benefit from genetic testing. Future efforts should validate and refine these criteria and search for other germline mutations associated with mesothelioma and related diseases.

Patterns of survival in patients with recurrent mantle cell lymphoma in the modern era: progressive shortening in response duration and survival after each relapse.

As the survival of patients with mantle cell lymphoma (MCL) continues to improve, patients are increasingly being treated with multiple regimens. However, outcome after each line remains poorly characterized in the modern era. To address this knowledge gap, we retrospectively studied 404 consecutive MCL patients who were managed between 2000 and 2014 at Memorial Sloan Kettering Cancer Center. Histologic diagnosis was centrally confirmed, and patients were followed longitudinally from diagnosis throughout their disease course. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier method. The median OS and PFS after first-line treatment were 9.7 and 4.0 years, respectively. After second-line therapy, the median OS and PFS were 41.1 and 14.0 months, third line were 25.2 and 6.5 months, and fourth line were 14.4 and 5.0 months. In patients less than 65 years, stem cell transplant (SCT)-based frontline regimens were associated with improved PFS compared with non-SCT regimens (median PFS: 86.2 versus 40.0 months; P < 0.01), with a trend toward longer OS (median OS: 165.0 versus 120.0 months; P = 0.06). Early treatment failure after first-line regimens was associated with worse OS (5.9 versus 2.5 years; P < 0.01). Our study should facilitate establishing proper endpoints for future clinical trials using novel treatment approaches.

Role of imaging in low-grade cutaneous B-cell lymphoma presenting in the skin.

BACKGROUND: Whole-body imaging is the current standard of care for staging all patients presenting with skin lesions of B-cell lymphomas (BCLs), regardless of skin disease extent; however, supporting data are lacking. OBJECTIVE: To determine the clinical utility of imaging in the detection of systemic involvement in low-grade cutaneous BCLs in the skin. METHODS: Retrospective cohort analysis of patients presenting with cutaneous lesions of BCLs at Memorial Sloan Kettering Cancer Center and Stanford University during 1997-2016. RESULTS: At initial staging, of the 522 patients, extracutaneous disease was noted in 3.6% and 8.8% of patients with marginal zone lymphoma (MZL, n = 306) and follicle center lymphoma (FCL, n = 216) histology, respectively. In patients with systemic involvement, imaging alone identified 81.8% (9/11) of MZL cases and 89.4% of follicular lymphoma cases. In primary cutaneous MZL, 1.7% of patients subsequently had extracutaneous involvement (median follow-up 45 months), and in primary cutaneous FCL. 3.0% subsequently had extracutaneous involvement (median follow-up 47 months). LIMITATIONS: This was a retrospective study. CONCLUSION: Imaging is effective at identifying patients with systemic involvement in indolent BCLs present in the skin; however, incidence is low. After negative initial staging, primary cutaneous MZL patients may be followed clinically without routine imaging.

A Prospective Study of Circulating Tumor DNA to Guide Matched Targeted Therapy in Lung Cancers.

BACKGROUND: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) is commercially available and increasingly adopted in clinical practice despite a paucity of prospective data to support its use. METHODS: Patients with advanced lung cancers who had no known oncogenic driver or developed resistance to current targeted therapy (n = 210) underwent plasma NGS, targeting 21 genes. A subset of patients had concurrent tissue NGS testing using a 468-gene panel (n = 106). Oncogenic driver detection, test turnaround time (TAT), concordance, and treatment response guided by plasma NGS were measured. All statistical tests were two-sided. RESULTS: Somatic mutations were detected in 64.3% (135/210) of patients. ctDNA detection was lower in patients who were on systemic therapy at the time of plasma collection compared with those who were not (30/70, 42.9% vs 105/140, 75.0%; OR = 0.26, 95% CI = 0.1 to 0.5, P < .001). The median TAT of plasma NGS was shorter than tissue NGS (9 vs 20 days; P < .001). Overall concordance, defined as the proportion of patients for whom at least one identical genomic alteration was identified in both tissue and plasma, was 56.6% (60/106, 95% CI = 46.6% to 66.2%). Among patients who tested plasma NGS positive, 89.6% (60/67; 95% CI = 79.7% to 95.7%) were also concordant on tissue NGS and 60.6% (60/99; 95% CI = 50.3% to 70.3%) vice versa. Patients who tested plasma NGS positive for oncogenic drivers had tissue NGS concordance of 96.1% (49/51, 95% CI = 86.5% to 99.5%), and directly led to matched targeted therapy in 21.9% (46/210) with clinical response. CONCLUSIONS: Plasma ctDNA NGS detected a variety of oncogenic drivers with a shorter TAT compared with tissue NGS and matched patients to targeted therapy with clinical response. Positive findings on plasma NGS were highly concordant with tissue NGS and can guide immediate therapy; however, a negative finding in plasma requires further testing. Our findings support the potential incorporation of plasma NGS into practice guidelines.

Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers.

PURPOSE: Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade (ICB). The impact of TMB on outcomes with targeted therapies has not been explored. EXPERIMENTAL DESIGN: We identified all patients with metastatic EGFR exon19del or L858R-mutant lung cancers treated with first/second-generation EGFR tyrosine kinase inhibitors (TKIs) with pretreatment next-generation sequencing data (MSK-IMPACT assay). The effect of TMB on time-to-treatment discontinuation (TTD) and overall survival (OS) were evaluated in univariate and multivariate analyses. EGFR wild-type lung adenocarcinoma samples were used for comparison. RESULTS: Among 153 patients with EGFR-mutant lung cancer, TMB was lower compared with EGFR wild-type (n = 1,849; median 3.77 vs. 6.12 mutations/Mb; P < 0.0001) with a broad range (0.82-17.9 mutations/Mb). Patients with EGFR-mutant lung cancer whose tumors had TMB in the high tertile had shorter TTD (HR, 0.46; P = 0.0008) and OS (HR, 0.40; P = 0.006) compared with patients with low/intermediate TMB. Evaluating by median TMB, there was significantly shorter TTD and OS for patients with higher TMB (TTD, P = 0.006; OS, P = 0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared with high TMB (HR = 0.57, P = 0.01; HR = 0.50, P = 0.02, respectively). In paired pretreatment and postprogression samples, TMB was increased at resistance (median 3.42 vs. 6.56 mutations/Mb; P = 0.008). CONCLUSIONS: TMB is negatively associated with clinical outcomes in metastatic patients with EGFR-mutant lung cancer treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy.See related commentary by Cheng and Oxnard, p. 899.

Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer.

PURPOSE: Treatment with programmed cell death-1 or programmed death ligand 1 (PD-(L)1) inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of corticosteroids may reduce efficacy of PD-(L)1 blockade. On-treatment corticosteroids for treatment of immune-related adverse events do not seem to affect efficacy, but the potential impact of baseline corticosteroids at the time of treatment initiation is unknown. Clinical trials typically excluded patients who received baseline corticosteroids, which led us to use real-world data to examine the effect of corticosteroids at treatment initiation. METHODS: We identified patients who were PD-(L)1-naïve with advanced non-small-cell lung cancer from two institutions-Memorial Sloan Kettering Cancer Center and Gustave Roussy Cancer Center-who were treated with single-agent PD-(L)1 blockade. Clinical and pharmacy records were reviewed to identify corticosteroid use at the time of beginning anti-PD-(L)1 therapy. We performed multivariable analyses using Cox proportional hazards regression model and logistic regression. RESULTS: Ninety (14%) of 640 patients treated with single-agent PD-(L)1 blockade received corticosteroids of ≥ 10 mg of prednisone equivalent daily at the start of the PD-(L)1 blockade. Common indications for corticosteroids were dyspnea (33%), fatigue (21%), and brain metastases (19%). In both independent cohorts, Memorial Sloan Kettering Cancer Center (n = 455) and Gustave Roussy Cancer Center (n = 185), baseline corticosteroids were associated with decreased overall response rate, progression-free survival, and overall survival with PD-(L)1 blockade. In a multivariable analysis of the pooled population, adjusting for smoking history, performance status, and history of brain metastases, baseline corticosteroids remained significantly associated with decreased progression-free survival (hazard ratio, 1.3; P = .03), and overall survival (hazard ratio, 1.7; P < .001). CONCLUSION: Baseline corticosteroid use of ≥ 10 mg of prednisone equivalent was associated with poorer outcome in patients with non-small-cell lung cancer who were treated with PD-(L)1 blockade. Prudent use of corticosteroids at the time of initiating PD-(L)1 blockade is recommended.

Safety and Efficacy of Re-treating with Immunotherapy after Immune-Related Adverse Events in Patients with NSCLC.

Considering retreatment following recovery from an immune-related adverse event (irAE) is a common clinical scenario, but the safety and benefit of retreatment is unknown. We identified patients with advanced non-small cell lung cancer (NSCLC) treated with anti-PD-(L)1 who had treatment held due to irAEs and divided them into two groups: those retreated with anti-PD-(L)1 (retreatment cohort) or those who had treatment stopped (discontinuation cohort). Out of 482 NSCLC patients treated with anti-PD-(L)1, 68 (14%) developed a serious irAE requiring treatment interruption. Of these, 38 (56%) were retreated and 30 (44%) had treatment discontinued. In the retreatment cohort, 18 (48%) patients had no subsequent irAEs, 10 (26%) had recurrence of the initial irAE, and 10 (26%) had a new irAE. Most recurrent/new irAEs were mild (58% grade 1-2) and manageable (84% resolved or improved to grade 1). Two treatment-related deaths occurred. Recurrent/new irAEs were more likely if the initial irAE required hospitalization, but the initial grade and time to retreatment did not influence risk. Among those with no observed partial responses prior to the irAE, progression-free survival (PFS) and overall survival (OS) were longer in the retreatment cohort. Conversely, for those with objective responses prior to the irAE, PFS and OS were similar in the retreatment and discontinuation cohorts. Among patients with early objective responses prior to a serious irAE, outcomes were similar, whether or not they were retreated. Together, data suggest that benefit may occur with retreatment in patients with irAEs who had no treatment response prior to irAE onset. Cancer Immunol Res; 6(9); 1093-9. ©2018 AACR.

Outcomes of Relapsed and Refractory Primary Mediastinal (Thymic) Large B Cell Lymphoma Treated with Second-Line Therapy and Intent to Transplant.

Primary mediastinal (thymic) large B cell lymphoma is a subtype of diffuse large B cell lymphoma with distinct clinical, molecular, and genetic features, many of which overlap with Hodgkin lymphoma. Increasingly, initial therapy for these patients has used dose-dense chemotherapy with or without radiation with excellent results. In patients with relapsed and primary refractory disease, outcomes of second-line therapy followed by consolidation with high-dose therapy and autologous stem cell transplantation remains largely undefined. We reviewed the outcomes of 60 transplant-eligible patients with relapsed or refractory primary mediastinal (thymic) large B cell lymphoma enrolled on sequential protocols with uniform second-line therapy with intent to consolidate with autologous stem cell transplant. The estimated 3-year overall and event-free survivals for all patients were 61% and 57%, respectively, and 68% and 65%, respectively, for patients proceeding to stem cell transplant. Multivariable analysis of risk factors before transplant revealed that an incomplete response to initial therapy, advanced Ann Arbor stage at disease progression, and failure to achieve a partial remission or better to second-line therapy to be independently associated with inferior event-free and overall survival. A risk score based on these variables was able to identify patients who are unlikely to respond to conventional second-line strategies. These results suggest that salvage chemoradiotherapy with intent of subsequent high-dose therapy and autologous stem cell transplant is successful in most patients with relapsed and refractory primary mediastinal (thymic) large B cell lymphoma. Alternative strategies are warranted for a significant subset of patients with high-risk disease who are unlikely to be cured with this strategy.