Association Between Utilization of Services and Perioperative Outcomes for Lung Cancer Resection.

INTRODUCTION: Lung cancer resection has largely focused on perioperative outcomes (eg, mortality) to benchmark performance. While variations in perioperative outcomes and in utilization of services (eg, ambulatory procedures, hospitalization) have been independently demonstrated, there has been limited evaluation of associations between these outcomes. We evaluated the association between perioperative outcomes and utilization of services to evaluate provider performance across a broader context of care. PATIENTS AND METHODS: This was a retrospective cohort study of patients undergoing lung cancer resection in 2017 to 2019. We utilized hierarchical logistic regression models to determine risk- and reliability-adjusted mortality and risk-adjusted utilization of services, at the hospital-level. We then evaluated utilization of services across quartiles of perioperative mortality. RESULTS: A total of 15,168 patients across 297 hospitals underwent lung cancer resection. Mean risk- and reliability-adjusted 90-day mortality varied between 1.58% (95% CI, 1.54%-1.62%) and 2.74% (95% CI, 2.59%-2.90%) across quartiles. Risk-adjusted utilization of all ambulatory procedures was highest in the best performing (lowest mortality) quartile at 37.7% (95% CI, 33.6%-41.8%). Additionally, risk-adjusted inpatient utilization prior to and after surgery was lowest in the best performing quartile at 15% (95% CI, 13.7%-16.3%) and 19.3% (95% CI, 17.5%-21.0%), respectively. CONCLUSIONS: Hospitals with the lowest perioperative mortality demonstrated trends towards using more outpatient resources prior to surgery, but fewer inpatient services surrounding lung cancer resection. This correlation highlights the importance of incorporating utilization of services in addition to other metrics to profile the efficiency and effectiveness of centers performing lung cancer resection across a broader spectrum of care.

Long-term Remissions Following CD20-Directed Chimeric Antigen Receptor-Adoptive T-cell Therapy.

Chimeric antigen receptor (CAR) T-cell therapy produces high response rates in refractory B-cell non-Hodgkin lymphoma, but long-term data are minimal to date. In this study, we present long-term follow-up of a pilot trial testing a CD20-targeting third-generation CAR in patients with relapsed B-cell lymphomas following cyclophosphamide-only lymphodepletion. Two of the three patients in the trial, with mantle cell lymphoma and follicular lymphoma, had remissions lasting more than 7 years, though they ultimately relapsed. The absence of B-cell aplasia in both patients suggested a lack of functional CAR T-cell persistence, leading to the hypothesis that endogenous immune responses were responsible for these long-term remissions. Correlative immunologic analyses supported this hypothesis, with evidence of new humoral and cellular antitumor immune responses proximal to clinical response time points. Collectively, our results suggest that CAR T-cell therapy may facilitate epitope spreading and endogenous immune response formation in lymphomas. Significance: Two of three patients treated with CD20-targeted CAR T-cell therapy had long-term remissions, with evidence of endogenous antitumor immune response formation. Further investigation is warranted to develop conditions that promote epitope spreading in lymphomas.

Randomized Bendamustine-Rituximab(R) + Bortezomib Induction and R + Lenalidomide Maintenance for Mantle Cell Lymphoma.

While initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine-rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance following induction is often utilized. Thus, the open-label, randomized phase II ECOG-ACRIN Cancer Research Group E1411 trial was designed to test two questions: 1) Does addition of bortezomib to BR induction (BVR) and/or 2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012-2016, 373 previously untreated patients, 87% ≥ 60 years old, were enrolled in this trial. At a median follow up of 7.5 years, there is no difference in the median PFS of BR compared to BVR (5.5 yrs vs. 6.4 yrs, HR 0.90, 90% CI 0.70, 1.16). There were no unexpected additional toxicities with BVR treatment compared to BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide to rituximab did not significantly improve PFS, with median PFS in R vs LR (5.9 yrs vs 7.2 yrs, HR 0.84 90% CI 0.62, 1.15). The majority of patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with rituximab alone following BR. Nonetheless, the > 5 year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by rituximab maintenance as highly effective initial therapy for older MCL patients. (NCT01415752).

HA-1-targeted T cell receptor (TCR) T cell therapy for recurrent leukemia after hematopoietic stem cell transplantation.

Relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective anti-leukemic effect post-HCT. We conducted a phase I clinical trial employing a novel TCR-T product targeting the minor H antigen HA-1 to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T post-HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8-co-receptor were successfully manufactured from HA-1 disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to nine HCT recipients who had developed disease recurrence post-HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, four patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with one ongoing at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial is registered at clinicaltrials.gov as NCT03326921.

Ultra-deep mutational landscape in chronic lymphocytic leukemia uncovers dynamics of resistance to targeted therapies.

BTK inhibitors, Bcl-2 inhibitors, and other targeted therapies have significantly improved the outcomes of patients with chronic lymphocytic leukemia (CLL). With increased survivorship, monitoring disease and deciphering potential mechanisms of resistance to these agents are critical for devising effective treatment strategies. We used duplex sequencing, a technology that enables detection of mutations at ultra-low allelic frequencies, to identify mutations in five genes associated with drug resistance in CLL and followed their evolution in two patients who received multiple targeted therapies and ultimately developed disease progression on pirtobrutinib. In both patients we detected variants that expanded and reached significant cancer cell fractions (CCF). In patient R001, multiple known resistance mutations in both BTK and PLCG2 appeared following progression on zanubrutinib (BTK p.L528W, p.C481S; PLCG2 S707F, L845F, R665W, and D993H). In contrast, patient R002 developed multiple BTK mutations following acalabrutinib treatment, including known resistance mutations p.C481R, p.T474I and p.C481S. We found that pirtobrutinib was able to suppress, but not completely eradicate, BTK p.C481S mutations in both patients, but other resistance mutations such as mutations in PLCG2 and new BTK mutations increased while the patients were receiving pirtobrutinib. For example, BTK p.L528W in patient R001 increased in frequency more than 1,000-fold (from a CCF of 0.02% to 35%), and the CCF in p.T474I in patient R002 increased from 0.03% to 4.2% (more than 100-fold). Our data illuminate the evolutionary dynamics of resistant clones over the patients' disease course and under selective pressure from different targeted treatments.

Access to Guideline Concordant Care for Node-Positive Non-Small Cell Lung Cancer in the United States.

BACKGROUND: This study sought to determine whether seeking care at multiple Commission on Cancer (CoC) hospitals is associated with different rates of receiving guideline-concordant care (GCC) among patients with non-small cell lung cancer (NSCLC). METHODS: The National Cancer Database was queried for the years 2004 to 2018 for patients with margin-negative pT1 to pT3 N1 to N2 M0 noncarcinoid NSCLC without neoadjuvant therapy. GCC was defined as chemotherapy for pN1 disease and as chemotherapy with or without radiation for pN2 disease. Patients who received care at >1 facility were examined separately. Factors previously associated with barriers to care were compared between groups. Kaplan-Meier analysis with log-rank tests analyzed 5-year overall survival (OS). Propensity score matching was performed to compare the effect sizes of race, insurance status, and income. RESULTS: In total 44,531 patients met inclusion criteria, 11,980 (26.9%) of whom sought care at >1 CoC institution. Among patients with pN1 disease, 5565 (76.7%) received GCC if they visited >1 facility vs 13,995 (68.5%) patients who sought care at 1 facility (P < .001). For patients with pN2 disease, 3991 (84.4%) received GCC if they visited >1 facility vs9369 (77.4%) patients receiving care at 1 facility (P < .001). Visiting >1 facility was associated with higher OS at 5 years (4784 [54.35%] vs 10,215 [45.62%]; P < .001). CONCLUSIONS: Visiting >1 CoC institution is associated with higher rates of GCC for individuals with pN1 to pN2 lung cancer. Patients who received care at >1 facility had higher OS at 5 years. Further study is warranted to identify factors associated with the ability of patients to seek care at multiple facilities.

Upper Hemisternotomy Versus Full Sternotomy for Replacement of the Supracoronary Ascending Aorta and Aortic Valve.

OBJECTIVE: Upper hemisternotomy (UHS) for supracoronary ascending aorta replacement (scAAR) with concomitant aortic valve replacement (AVR) results in less trauma and potentially faster convalescence compared with full sternotomy (FS). Direct head-to-head studies are lacking. We compared a group of UHS patients with a matched group of FS patients undergoing scAAR and AVR. METHODS: There were 198 patients who underwent scAAR and AVR procedures by a single surgeon between 1999 and 2020. After matching 6 preoperative characteristics, there were 50 UHS and 50 FS patients. Patients who required acute type A aortic dissection repair, reoperations, concomitant procedures, or hypothermic circulatory arrest were excluded. RESULTS: In the matched sample, the hospital mortality rate was 1% (1 of 100). The median cardiopulmonary bypass time was 150 (interquartile range [IQR], 131 to 172) min and 164.5 (IQR, 138 to 190) min, respectively, for the UHS and FS groups (P = 0.08). The median aortic cross-clamp time was 121 (IQR, 107 to 139) min during UHS and 131 (IQR, 115 to 159) min during FS (P = 0.05). The median ventilation time was 7 (IQR, 3 to 14) h versus 17 (IQR, 10 to 24) h, respectively, after UHS and FS (P = 0.005). The median hospital length of stay was 7 (IQR, 6 to 9) days after UHS and 8 (IQR, 7 to 11) days after FS (P = 0.05). CONCLUSIONS: The low morbidity and mortality support the wider use of UHS for scAAR and AVR in appropriately selected patients. Larger studies are needed to confirm these initial findings.

Timing of anti-PD-L1 antibody initiation affects efficacy/toxicity of CD19 CAR T-cell therapy for large B-cell lymphoma.

ABSTRACT: More than half of the patients treated with CD19-targeted chimeric antigen receptor (CAR) T-cell immunotherapy for large B-cell lymphoma (LBCL) do not achieve durable remission, which may be partly due to PD-1/PD-L1-associated CAR T-cell dysfunction. We report data from a phase 1 clinical trial (NCT02706405), in which adults with LBCL were treated with autologous CD19 CAR T cells (JCAR014) combined with escalating doses of the anti-PD-L1 monoclonal antibody, durvalumab, starting either before or after CAR T-cell infusion. The addition of durvalumab to JCAR014 was safe and not associated with increased autoimmune or immune effector cell-associated toxicities. Patients who started durvalumab before JCAR014 infusion had later onset and shorter duration of cytokine release syndrome and inferior efficacy, which was associated with slower accumulation of CAR T cells and lower concentrations of inflammatory cytokines in the blood. Initiation of durvalumab before JCAR014 infusion resulted in an early increase in soluble PD-L1 (sPD-L1) levels that coincided with the timing of maximal CAR T-cell accumulation in the blood. In vitro, sPD-L1 induced dose-dependent suppression of CAR T-cell effector function, which could contribute to inferior efficacy observed in patients who received durvalumab before JCAR014. Despite the lack of efficacy improvement and similar CAR T-cell kinetics early after infusion, ongoing durvalumab therapy after JCAR014 was associated with re-expansion of CAR T cells in the blood, late regression of CD19+ and CD19- tumors, and enhanced duration of response. Our results indicate that the timing of initiation of PD-L1 blockade is a key variable that affects outcomes after CD19 CAR T-cell immunotherapy for adults with LBCL.

Pembrolizumab With R-CHOP in Previously Untreated DLBCL: Sustained, High Efficacy, and Safety With Long-Term Follow-Up.

BACKGROUND: While generally ineffective in relapsed diffuse large B cell lymphoma (DLBCL), immune checkpoint inhibitors (ICIs) may hold greater promise in untreated, immunocompetent patients. We previously reported safety and early efficacy of pembrolizumab plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (PR-CHOP) in a phase I trial of untreated DLBCL, noting responses in 90% of patients (complete response 77%) and a 2-year progression-free survival (PFS) of 83%. We herein report long-term safety and efficacy at 5-year follow up. PATIENTS AND METHODS: Adult patients with untreated DLBCL or grade 3b follicular lymphoma, intended to receive 6 cycles of R-CHOP were eligible. Patients (N = 30) were treated with pembrolizumab 200 mg IV and R-CHOP in 21-day cycles for 6 cycles. RESULTS: At median follow up of 4.8 years, 5-year PFS was 71% (CI, 54%-94%) and 5-year overall survival was 83% (CI, 71%-98%). Immune-related adverse events (IRAEs) occurred in 7 (23%) patients (10% grade 3/4). Three IRAEs (rash, thyroiditis, rheumatoid arthritis) occurred beyond 3 months of treatment completion. PD-L1 tumor expression was documented in 19 of 23 (83%) tested patients. None of the 19 patients who had any PD-L1 expression have relapsed, whereas 2 out of the 4 patients with no PD-L1 expression have relapsed. CONCLUSION: PR-CHOP has led to durable responses in most patients, with the best outcomes in PD-L1-expressing disease. Furthermore, the safety profile was manageable, with no consistent pattern of late events. These data support ongoing strategies incorporating ICIs in frontline DLBCL therapy and confirmation of predictive biomarkers including tumor PD-L1 expression.

Individual- and neighborhood-level characteristics of lung cancer screening participants undergoing telemedicine shared decision making.

BACKGROUND: Although lung cancer screening (LCS) for high-risk individuals reduces lung cancer mortality in clinical trial settings, many questions remain about how to implement high-quality LCS in real-world programs. With the increasing use of telemedicine in healthcare, studies examining this approach in the context of LCS are urgently needed. We aimed to identify sociodemographic and other factors associated with screening completion among individuals undergoing telemedicine Shared Decision Making (SDM) for LCS. METHODS: This retrospective study examined patients who completed Shared Decision Making (SDM) via telemedicine between May 4, 2020 - March 18, 2021 in a centralized LCS program. Individuals were categorized into Complete Screening vs. Incomplete Screening subgroups based on the status of subsequent LDCT completion. A multi-level, multivariate model was constructed to identify factors associated with incomplete screening. RESULTS: Among individuals undergoing telemedicine SDM during the study period, 20.6% did not complete a LDCT scan. Bivariate analysis demonstrated that Black/African-American race, Medicaid insurance status, and new patient type were associated with greater odds of incomplete screening. On multi-level, multivariate analysis, individuals who were new patients undergoing baseline LDCT or resided in a census tract with a high level of socioeconomic deprivation had significantly higher odds of incomplete screening. Individuals with a greater level of education experienced lower odds of incomplete screening. CONCLUSIONS: Among high-risk individuals undergoing telemedicine SDM for LCS, predictors of incomplete screening included low education, high neighborhood-level deprivation, and new patient type. Future research should focus on testing implementation strategies to improve LDCT completion rates while leveraging telemedicine for high-quality LCS.

Is wedge a dirty word? Demographic and facility-level variables associated with high-quality wedge resection.

Objectives: Although sublobar resections have gained traction, wedge resections vary widely in quality. We seek to characterize the demographic and facility-level variables associated with high-quality wedge resections. Methods: The National Cancer Database was queried from 2010 to 2018. Patients with T1/T2 N0 M0 non-small cell lung cancer 2 cm or less who underwent wedge resection without neoadjuvant therapy were included. A wedge resection with no nodes sampled or with positive margins was categorized as a low-quality wedge. A wedge resection with 4 or more nodes sampled and negative margins was categorized as a high-quality wedge. Facility-specific variables were investigated via quartile analysis based on the overall volume and proportion of high-quality wedge or low-quality wedge resections performed. Results: A total of 21,742 patients met inclusion criteria, 6390 (29.4%) of whom received a high-quality wedge resection. Factors associated with high-quality wedge resection included treatment at an academic center (3005 [47.0%] vs low-quality wedge 6279 [40.9%]; P < .001). The 30- and 90-day survivals were similar, but patients who received a high-quality wedge resection had improved 5-year survival (4902 [76.7%] vs 10,548 [68.7%]; P < .001). Facilities in the top quartile by volume of high-quality wedge resections performed 69% (4409) of all high-quality wedge resections, and facilities in the top quartile for low-quality wedge resections performed 67.6% (10,378) of all low-quality wedge resections. A total of 113 facilities were in the top quartile by volume for both high-quality wedge and low-quality wedge resections. Conclusions: High-quality wedge resections are associated with improved 5-year survival when compared with low-quality wedge resections. By volume, high-quality wedge and low-quality wedge resections cluster to a minority of facilities, many of which overlap. There is discordance between best practice guidelines and current practice patterns that warrants additional study.

Factors associated with long-term outcomes of CD19 CAR T-cell therapy for relapsed/refractory CLL.

High response rates have been reported after CD19-targeted chimeric antigen receptor-modified (CD19 CAR) T-cell therapy for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), yet the factors associated with duration of response in this setting are poorly characterized. We analyzed long-term outcomes in 47 patients with R/R CLL and/or Richter transformation treated on our phase 1/2 clinical trial of CD19 CAR T-cell therapy with an updated median follow-up of 79.6 months. Median progression-free survival (PFS) was 8.9 months, and the 6-year PFS was 17.8%. Maximum standardized uptake value (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.07-1.23; P < .001) and bulky disease (≥5 cm; HR, 2.12; 95% CI, 1.06-4.26; P = .034) before lymphodepletion were associated with shorter PFS. Day +28 complete response by positron emission tomography-computed tomography (HR, 0.13; 95% CI, 0.04-0.40; P < .001), day +28 measurable residual disease (MRD) negativity by multiparameter flow cytometry (HR, 0.08; 95% CI, 0.03-0.22; P < .001), day +28 MRD negativity by next-generation sequencing (HR, 0.21; 95% CI, 0.08-0.51; P < .001), higher peak CD8+ CAR T-cell expansion (HR, 0.49; 95% CI; 0.36-0.68; P < .001), higher peak CD4+ CAR T-cell expansion (HR, 0.47; 95% CI; 0.33-0.69; P < .001), and longer CAR T-cell persistence (HR, 0.56; 95% CI, 0.44-0.72; P < .001) were associated with longer PFS. The 6-year duration of response and overall survival were 26.4% and 31.2%, respectively. CD19 CAR T-cell therapy achieved durable responses with curative potential in a subset of patients with R/R CLL. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

Intraoperative Versus Preoperative Diagnosis of Lung Cancer: Differences in Treatments and Patient Outcomes.

OBJECTIVES: Non-small cell lung cancer (NSCLC) is frequently diagnosed during surgical resection. It remains unclear if lack of preoperative tissue diagnosis influences likelihood of receipt of guideline-concordant care or postoperative outcomes. METHODS: A retrospective cohort analysis was completed utilizing the National Cancer Database for patients undergoing lung resection with clinical stage 1 NSCLC from 2004 to 2018. Diagnosis during resection was defined as zero days between diagnosis and definitive lung resection. Patients receiving neoadjuvant therapy were excluded. Subgroup analyses were completed by resection type, including wedge resection. RESULTS: The cohort included 91,328 patients, 33,517 diagnosed during definitive resection and 57,811 diagnosed preoperatively. For patients diagnosed preoperatively, median time from diagnosis to surgery was 42 days (interquartile range 28-63 days). Patients diagnosed intraoperatively had smaller median tumor size (1.7 cm vs. 2.5 cm, P < .01) and were more likely to undergo wedge resection (10,668 [31.8%] vs. 7,617 [13.2%], P < .01). Intraoperative diagnosis resulted in lower likelihood of nodal sampling (27,356 [81.9%] vs. 53,183 [92.4%], P < .01) and nodal upstaging (2,482 [9.7%] vs. 7701 [15.5%], P < .01). Amongst patients with intraoperative diagnoses, those treated via wedge resection were less likely to undergo lymph node sampling (5,515 [52.0%] vs. 5,606 [61.1%], P < .01). Amongst patients with positive lymph nodes, patients diagnosed intraoperatively were less likely to receive adjuvant therapy (1,677 [5.0%] vs. 5,669 [9.8%], P < .01). CONCLUSIONS: Preoperative tissue diagnosis of NSCLC is associated with more frequent lymph node harvest, increased rates of upstaging and receipt of adjuvant therapy. Preoperative workup may contribute to increased rates of guideline-concordant lung cancer care.

γ-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial.

BACKGROUND: γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma. METHODS: We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 106 CAR T cells, 150 × 106 CAR T cells, 300 × 106 CAR T cells, and 450 × 106 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals. FINDINGS: 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 106 CAR+ cells, and the recommended phase 2 dose was not reached. INTERPRETATIONS: Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials. FUNDING: Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health.

Concurrent pembrolizumab with AVD for untreated classic Hodgkin lymphoma.

Concurrent administration of pembrolizumab with chemotherapy in untreated classic Hodgkin lymphoma (CHL) has not been studied previously. To investigate this combination, we conducted a single-arm study of concurrent pembrolizumab with AVD (doxorubicin, vinblastine, and dacarbazine; APVD) for untreated CHL. We enrolled 30 patients and met the primary safety end point with no observed significant treatment delays in the first 2 cycles. Twelve patients experienced grade 3 or 4 nonhematologic adverse events (AEs), most commonly febrile neutropenia and infection/sepsis. Grade 3 or 4 immune-related AEs, including alanine aminotransferase elevation and aspartate aminotransferase elevation were observed in 3 patients. One patient experienced an episode of grade 2 colitis and arthritis. Six patients missed at least 1 dose of pembrolizumab because of AEs, primarily grade 2 or higher transaminitis. Among 29 response-evaluable patients, the best overall response rate was 100% and the complete response rate was 90%. With a median follow-up of 2.1 years, the 2-year progression-free survival (PFS) and overall survival were 97% and 100%, respectively. To date, no patient who has withheld or discontinued pembrolizumab because of toxicity has progressed. Clearance of circulating tumor DNA (ctDNA) was associated with superior PFS when measured after cycle 2 and at the end of treatment (EOT). None of the 4 patients with persistent uptake by fluorodeoxyglucose positron emission tomography (PET) at EOT yet negative ctDNA have relapsed to date. Concurrent APVD shows promising safety and efficacy but may yield spurious PET findings in some patients. This trial was registered at www.clinicaltrials.gov as #NCT03331341.

Defining risk factors for mortality after emergent hiatal hernia repair in the era of minimally invasive surgery.

BACKGROUND: Risk factors for mortality following emergent hiatal hernia (HH) repair in the era of minimally invasive surgery remain poorly defined. METHODS: Data was obtained from the National Inpatient Sample (NIS), National Readmissions Database, and National Emergency Department Sample for patients undergoing HH repair between 2010 and 2018. Univariate and multivariate logistic regression analyses reported with odds ratio (OR) and 95% confidence intervals (CI) were performed to identify factors associated mortality. RESULTS: Via the NIS, mortality rate was 2.2% (147 patients). Via the NEDS, the mortality rate was 3.6% (303 patients). On multivariate analysis, predictors of mortality included age (OR 1.05, CI: 1.04,1.07), male sex (OR 1.49, CI: 1.06,2.11), frailty (OR 2.49, CI: 1.65,3.75), open repair (OR 3.59, CI: 2.50,5.17), and congestive heart failure (OR 2.71, CI: 1.81,4.06). CONCLUSIONS: There are multiple risk factors for mortality after hiatal hernia repair. There is merit to a laparoscopic approach even in emergent settings.

Impact of stereotactic body radiation therapy volume on surgical patient selection, short-term survival, and long-term survival in early-stage non-small cell lung cancer.

OBJECTIVES: Stereotactic body radiation therapy (SBRT) is increasingly used to treat non-small cell lung cancer. The purpose of this study is to analyze relationships between facility SBRT utilization and surgical patient selection and survival after surgery. METHODS: Data on patients with TI/T2N0M0 lesions and treatment facility characteristics were abstracted from the National Cancer Database, 2008 to 2017. Facilities were stratified using an SBRT/surgery ratio previously associated with short-term survival benefit for patients treated surgically, and by a previously identified surgical volume threshold. Multiple regression analyses, Cox proportional-hazard regressions, and Kaplan-Meier log rank test were employed. RESULTS: In total, 182,610 patients were included. Proportion of high SBRT:surgery ratio (≥17%) facilities increased from 118 (11.5%) to 558 (48.4%) over the study period. Patients undergoing surgery at high-SBRT facilities had comparable comorbidity scores and tumor sizes to those at low-SBRT facilities, and nonclinically significant differences in age, race, and insurance status. Among low-volume surgical facilities, treatment at a high SBRT-using facility was associated with decreased 30-day mortality (1.8% vs 1.4%, P < .001) and 90-day mortality (3.3% vs 2.6%, P < .001). At high-volume surgical facilities, no difference was observed. At 5 years, a survival advantage was identified for patients undergoing resection at facilities with high surgical volumes (hazard ratio, 0.91; confidence interval, 0.90-0.93 P < .001) but not at high SBRT-utilizing facilities. CONCLUSIONS: Differences in short-term survival following resection at facilities with high-SBRT utilization may be attributable to low surgical volume facilities. Patients treated at high volume surgical facilities do not demonstrate differences in short-term or long-term survival based on facility SBRT utilization.