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Purpose:This phase 1 study (NCT03440437) evaluated the safety, tolerability, pharmacokinetics (PK), and activity of FS118, a bispecific antibody–targeting LAG-3 and PD-L1, in patients with advanced cancer resistant to anti–PD-(L)1 therapy.Patients and Methods:Patients with solid tumors, refractory to anti–PD-(L)1–based therapy, received intravenous FS118 weekly with an accelerated dose titration design (800 μg to 0.3 mg/kg) followed by 3+3 ascending dose expansion (1 to 20 mg/kg). Primary objectives were safety, tolerability, and PK. Additional endpoints included antitumor activity, immunogenicity, and pharmacodynamics.Results:Forty-three patients with a median of three prior regimens in the locally advanced/metastatic setting, including at least one anti–PD-(L)1 regimen, received FS118 monotherapy. FS118 was well tolerated, with no serious adverse events relating to FS118 reported. No dose-limiting toxicities (DLT) were observed, and an MTD was not reached. The recommended phase 2 dose of FS118 was established as 10 mg/kg weekly. The terminal half-life was 3.9 days. Immunogenicity was transient. Pharmacodynamic activity was prolonged throughout dosing as demonstrated by sustained elevation of soluble LAG-3 and increased peripheral effector cells. The overall disease control rate (DCR) was 46.5%; this disease control was observed as stable disease, except for one late partial response. Disease control of 54.8% was observed in patients receiving 1 mg/kg or greater who had acquired resistance to PD-(L)1–targeted therapy.Conclusions:FS118 was well tolerated with no DLTs observed up to and including 20 mg/kg QW. Further studies are warranted to determine clinical benefit in patients who have become refractory to anti–PD-(L)1 therapy.See related commentary by Karapetyan and Luke, p. 835

Background Abdominal visceral resections incur relatively higher rates of postoperative bleeding and venous thromboembolism (VTE). While guidelines recommend the use of perioperative chemical thromboprophylaxis, the most appropriate time for its initiation is unknown. Here, we investigated whether early (before skin closure) versus postoperative commencement of chemoprophylaxis affected VTE and bleeding rates following abdominal visceral resection. Methods Retrospective review of all elective abdominal visceral resections undertaken between January 1, 2018, and June 30, 2019, across four tertiary-referral hospitals. Major bleeding was defined as the need for blood transfusion, reintervention, or > 20 g/L fall in hemoglobin from baseline. Clinical VTE was defined as imaging-proven symptomatic disease Results A total of 945 cases were analyzed. Chemoprophylaxis was given early in 265 (28.0%) patients and postoperatively in 680 (72.0%) patients. Mean chemoprophylaxis exposure doses were similar between the two groups. Clinical VTE developed in 14 (1.5%) patients and was unrelated to chemoprophylaxis timing. Postoperative bleeding occurred in 71 (7.5%) patients, with 57 (80.3%) major bleeds, requiring blood transfusion in 48 (67.6%) cases and reintervention in 31 (43.7%) cases. Bleeding extended length-of-stay (median (IQR), 12 (7–27) versus 7 (5–11) days, p p = 0.038) and independently predicted its occurrence. Conclusions The risk of bleeding following elective abdominal visceral resections is substantial and is higher than the risk of clinical VTE. Compared with early chemoprophylaxis, postoperative initiation reduces bleeding risk without an increased risk of clinical VTE.

Simulation is an important tool in surgical training. However, the transferability of skills obtained in the simulation setting to the operating room (OR) is uncertain. This study explores the association between resident simulation performance and OR performance in a laparoscopic cholecystectomy (LC) simulation module.A simulation module focused on LC utilizing a virtual reality simulator was completed by general surgery residents. Simulation performance was evaluated using the validated Global Operative Assessment of Laparoscopic Skills (GOALS) and Objective Structured Assessment of Technical Skills (OSATS), as well as a LC-specific simulation assessment form (LC-SIM). Resident subsequent OR performances of LC were measured by the Surgical Training and Assessment Tool (STAT), an online mobile-based evaluation completed by attending surgeons.Twenty-one residents who completed the simulation module and also with STAT data on LC from 2016 to 2020 were included. Higher scores on incision/port placement on LC-SIM is associated with better tissue handling (coefficient 0.20, p = 0.048) and better timeeconomy of motion on STAT (coefficient 0.22, p = 0.037). However, higher scores on time and motion on OSATS are associated with worse tissue handling (- 0.28, p = 0.046), worse timeeconomy of motion (- 0.37, p = 0.009), and worse overall grade (- 0.21, p = 0.044). Higher scores on overall performance on OSATS is associated with worse timeeconomy of motion (- 0.80, p = 0.008). Higher scores on depth perception on GOALS are associated with worse tissue handling (- 0.28, p = 0.044).We found significant positive and negative associations between resident simulation performance and OR performance, particularly in tissue handling and economy of motion. This could suggest that simulation performance does not reliably predict OR performance. However, this could highlight the concept of excessive caution in the real OR environment and longer operative time which could be interpreted as worse time and economy of motion by the attending surgeons.

Purpose: To determine whether SD-101, a Toll-like receptor 9 agonist, potentiates the antitumor activity of anti-PD-1 antibodies in patients with anti-PD-1/PD-L1 naïve, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients and Methods: Patients with PD-1 Ab-naïve HNSCC received either 2 mg SD-101 injected in one to four lesions or 8 mg SD-101 injected into a single lesion weekly × 4 doses then every 3 weeks × 7 doses. Pembrolizumab was administered at 200 mg every 3 weeks. Results: A total of 28 patients received 2 mg and 23 received 8 mg per injection, respectively. A total of 76% of patients had received prior systemic therapy. Combined positive score was ≥1 to < 20 in 35 patients (70%) and ≥ 20 in 15 patients (30%) of 50 patients with available data. There were 12 patients with grade ≥3 treatment-related adverse events (24%), and no treatment-related deaths. The objective response rate was 24% including 2 complete and 10 partial responses. The median duration of response was 7.0 [95% confidence interval (CI): 2.1–11.1] months. The response rate was higher in human papillomavirus–positive (HPV+) patients (44%, N = 16). Responses were not associated with PD-L1 expression levels or IFNγ-related gene expression at baseline. Responses were observed both in injected (32%) and in noninjected lesions (29%). Progression-free and overall survival at 9 months were 19.0% (95% CI: 9.1–31.7) and 64.7% (95% CI: 45.3–78.7), respectively. Conclusions: SD-101 combined with pembrolizumab induced objective responses, especially in HPV+ tumors, which were frequently associated with increased intratumoral inflammation and effector immune cell activity.

The functional lumen imaging probe provides objective measurements of the gastroesophageal junction during laparoscopic anti-reflux surgery. There is a lack of data on how functional lumen imaging probe measurements change at follow-up. We aim to describe our institutional experience in performing functional lumen imaging probe during postoperative endoscopy after laparoscopic anti-reflux surgery.A prospectively maintained database was queried. Patients who had postoperative endoscopic functional lumen imaging probe measurements between March 2018 and June 2021 were assessed at different time points from their index laparoscopic anti-reflux surgery using paired t test. Standardized quality of life questionnaires were collected for up to 2 years. Group comparisons were made using the Wilcoxon rank-sum test.Fifty-eight patients who underwent laparoscopic anti-reflux surgery (magnetic sphincter augmentation or fundoplication) had postoperative functional lumen imaging probe. Thirty-two intraoperative functional lumen imaging probe values were compared with their postoperative functional lumen imaging probe. Fundoplication values did not differ. Postoperative functional lumen imaging probe distensibility index for magnetic sphincter augmentation patients was decreased (P = .04). Functional lumen imaging probe measurements for all postoperative endoscopies showed that magnetic sphincter augmentation had the lowest distensibility index (P.01). Dysphagia as a reason for endoscopy had a decrease in distensibility index (P = .03).Functional lumen imaging probe measurements after fundoplication persist at long-term follow up while patients may have a tighter gastroesophageal junction after magnetic sphincter augmentation. Functional lumen imaging probe has the potential to assess the success or failure after laparoscopic anti-reflux surgery and optimize patient outcomes.

Objective : Catholic Religious and Ethical Directives restrict access to contraception, yet offering contraception during a delivery hospitalization facilitates birth spacing and is a convenient option for patients during the postpartum period. We assessed patient and provider experiences with hospital transparency around postpartum contraceptive care in Illinois Catholic hospitals. Study Design : We interviewed 44 participants with experience in Illinois Catholic hospitals: 21 patients, and 23 providers, including clinicians, nurses, doulas, and postpartum program staff. We used an open-ended interview approach, with a semi-structured guide focused on postpartum contraceptive care. We conducted interviews by phone between November 2019 and June 2020. We audio-recorded interviews, transcribed them verbatim, and coded transcripts in Dedoose. We developed narrative memos for each code, identifying themes and sub-themes. We organized these in a matrix for analysis and present here themes regarding hospital transparency that emerged across interviews. Results : Many patients knew they were delivering in a Catholic hospital; however, few were aware that Catholic policies limited their healthcare options. Patients expressed a desire for hospitals to be transparent, even “very vocal,” about religious restrictions and described consequences of restrictions on patient care. Patients lacked information to make contraceptive decisions, experienced limits on or delays in care, and some lost continuity with trusted providers. Consequences for providers included moral distress in trying to provide care using workarounds such as documenting false medical diagnoses. Conclusions : Religious restrictions on postpartum contraception restrict access, cause unnecessary delays in care, and lead to misdiagnosis and marginalization of contraceptive care. Restrictions also cause moral distress to providers who balance career repercussions and professional integrity with patient needs. Implications : To protect patient autonomy, especially during the vulnerable postpartum period, Catholic hospitals should increase transparency regarding limitations on reproductive health care. Insurers and policy-makers should guarantee that patients have the option to receive care at hospitals without these limitations and facilitate public education about what to expect at Catholic facilities.

Obtaining a clear Critical View of Safety helps prevent bile duct injuries during laparoscopic cholecystectomy, which can be improved with a structured Safe Critical View of Safety curriculum. We aimed to determine whether the improvement in obtaining Critical View of Safety postcurriculum is retained long-term.A safe Critical View of Safety curriculum was previously implemented for all surgeons who perform laparoscopic cholecystectomy at a regional health system. Recordings of laparoscopic cholecystectomy cases were collected 1 year after completion of the curriculum, deidentified and randomly ordered, and then graded by 2 blinded expert surgeons using a 6-point Critical View of Safety assessment tool.A total of 12 surgeons with average experience of 17.9 ± 6.3 years in practice participated in the study. The majority (83%) had performed700 laparoscopic cholecystectomies, and 4 surgeons (33%) reported 2 or more bile duct injuries in their career. Controlling for gallbladder pathology, Critical View of Safety scores improved from 1.7 ± 0.4 to 4.0 ± 0.4 (P.001) immediately after completion of the curriculum. However, there was a small decrease in Critical View of Safety score after 1 year (3.2 ± 0.3 from 4.0 ± 0.4, P = .055), while still significantly higher compared to precurriculum (3.2 ± 0.3 vs 1.7 ± 0.4, P.001). Acute care surgeons had lower Critical View of Safety retention scores compared to general surgeons (1.8 ± 0.5 vs 3.3 ± 0.4, P = .01) and minimally invasive surgeons (1.8 ± 0.5 vs 3.8 ± 0.5, P.01).A structured curriculum helped improve practicing surgeons' attainment of obtaining the Critical View of Safety during laparoscopic cholecystectomy. However, this improvement decreased after 1 year, suggesting some decay in knowledge retention over time. Therefore, continued educational interventions on Critical View of Safety and safe laparoscopic cholecystectomy may be needed to enhance long-term retention.

Grey gneisses from the Tokwe and Rhodesdale terrains of the Zimbabwe craton have zircon ages of ~3.63, 3.52, and 3.34 Ga, validating the existence of Eo- to Palaeoarchaean crust. In-situ zircon Hf isotope compositions reveal the interplay between episodes of juvenile magma addition, crustal thickening and crustal differentiation. Starting from juvenile mafic crust (with chondritic composition) at ~3.9 Ga, the oldest nucleus of the Zimbabwe craton developed into a stable crustal block by ~3.35 Ga, following a tectonic and mantle evolution that is mirrored by other ancient terrains.

Purpose Older adults with head and neck cancer have increased postoperative complications, longer hospital stays, and higher rates of mortality. Geriatric assessment (GA) provides a measure of overall health status and is preferable to using age alone for assessing fitness for surgery. We sought to determine whether a patient's frailty as determined by a novel electronic GA is associated with outcomes after head and neck cancer (HNC) surgery. Methods We conducted a retrospective review of 159 patients aged 75 and older referred to the Geriatrics Service at Memorial Sloan Kettering Cancer Center for pre-operative evaluation prior to undergoing HNC surgery. All patients completed the electronic Rapid Fitness Assessment (eRFA) within 60 days prior to surgery. The accumulated geriatric deficit (AGD) score includes twelve domains from the eRFA with a point assigned for each domain in which there is a deficit and a final point related to comorbidities. Three other metrics were individually assessed: age, Karnofsky Performance Scale (KPS), and number of comorbidities. We utilized multivariable linear regression and t-tests to determine whether frailty is associated with longer length of hospital stay, 30-day intensive care unit (ICU) admission, and 30-day and 90-day postoperative mortality. Results Patients with a higher AGD score spent more time in the hospital post-operatively (1.0 day increase per unit increase in AGD; 95% CI: 0.21–1.9; p = 0.015). Lower KPS was also associated with statistically significant longer length of stay (−2.70 day change per increasing index KPS; 95% CI: −4.30 – −1.00; days; p = 0.002), while age and comorbidity were not found to be statistically associated with length of stay. Higher AGD score remained significantly associated with longer length of stay on multivariable analysis (0.93 day increase per unit increase in AGD; 95% CI 0.15–1.71; p = 0.019). AGD was the only metric associated with increased risk of ICU admission (6.6 vs 5.0 geriatric deficits for those admitted vs not admitted to ICU; p = 0.024). Conclusions Frailty is associated with increased length of hospital stay and ICU admission in older adults with HNC undergoing surgery. GA can be used to counsel patients on the expected postoperative course.

Nonalcoholic fatty liver disease (NAFLD) affects more than 25% of the adult population worldwide and is associated with significant clinical and economic burden.1 However, heterogeneous definitions and inaccurate terminology contribute to variations in prevalence estimates and may not comprehensively incorporate complex metabolic dysfunctions that exist. An international expert panel consensus proposed updated nomenclature, metabolic dysfunction-associated fatty liver disease (MAFLD), and associated criteria to more accurately capture this complex multisystem metabolic disorder.2 Although it has not replaced NAFLD, the term MAFLD has been positively received given it more comprehensively incorporates the metabolic derangements that contribute to risk of fatty liver and it may be more practical for clinicians to identify patients with fatty liver.3 We describe prevalence of MAFLD among US adults based on these recently proposed nomenclature and definition.2.

Functional luminal imaging probe (FLIP) use during laparoscopic fundoplication (LF) for gastroesophageal reflux disease is well described. However, there is a lack of data on FLIP measurements during magnetic sphincter augmentation (MSA). This study aims to report our institutional experience in performing FLIP during MSA and to compare these measurements to those obtained during Nissen and Toupet fundoplication.A retrospective review of a prospectively maintained quality database was performed. Patients who underwent MSA or LF and had FLIP measurements between April 2018 and June 2021 were included. FLIP measurements at the gastroesophageal junction (GEJ) were recorded without pneumoperitoneum at 40 mL balloon fill after hernia reduction, cruroplasty, and MSA or fundoplication. Reflux symptom index (RSI), GERD-HRQL, and dysphagia score were collected up to 2 years. Group comparisons were made using two-tailed Wilcoxon rank-sum and χTwenty-seven patients underwent MSA and 100 patients underwent LF (66% Toupet, 34% Nissen). Type III hiatal hernia was present in 3.7% of MSA patients versus over 50% for fundoplication patients. Minimum diameter, cross-sectional area, and distensibility index (DI) were lower after MSA device placement compared to Nissen or Toupet fundoplication (p 0.05). Postoperative follow-up showed no differences in RSI, GERD-HRQL, and dysphagia score between MSA and Nissen fundoplication (p 0.05).Intraoperative impedance planimetry provided objective information regarding the geometry of the GEJ during MSA. The ring of magnetic beads restores the anti-reflux barrier and transiently opens with food bolus and belching. The magnetic force of the beads may explain why the DI after MSA is lower yet postoperative quality of life is no different than Nissen fundoplication.

Liquid biopsies that measure circulating cell-free RNA (cfRNA) offer an opportunity to study the development of pregnancy-related complications in a non-invasive manner and to bridge gaps in clinical care1–4. Here we used 404 blood samples from 199 pregnant mothers to identify and validate cfRNA transcriptomic changes that are associated with preeclampsia, a multi-organ syndrome that is the second largest cause of maternal death globally5. We find that changes in cfRNA gene expression between normotensive and preeclamptic mothers are marked and stable early in gestation, well before the onset of symptoms. These changes are enriched for genes specific to neuromuscular, endothelial and immune cell types and tissues that reflect key aspects of preeclampsia physiology6–9, suggest new hypotheses for disease progression and correlate with maternal organ health. This enabled the identification and independent validation of a panel of 18 genes that when measured between 5 and 16 weeks of gestation can form the basis of a liquid biopsy test that would identify mothers at risk of preeclampsia long before clinical symptoms manifest themselves. Tests based on these observations could help predict and manage who is at risk for preeclampsia—an important objective for obstetric care10,11.

Background: Telehealth, especially the use of real-time video and phone visits in ambulatory care, is increasingly important in the wake of the COVID-19 pandemic. The current state of internal medicine (IM) interns' telehealth training at the start of residency is unknown. Objective: To characterize the attitudes, training, and preparedness of IM interns regarding the use of telehealth video and phone visits in ambulatory care. Methods: We conducted a cross-sectional survey of IM interns at four IM residency programs in the United States in 2020. Results: One hundred fifty-six surveys were analyzed (response rate 82%). Seventy-five percent of interns rated training in the use of real-time video and phone visits for ambulatory care as important or very important. The vast majority received no training (74%) or clinical experience (90% no prior video visits, 81% no prior phone visits) during medical school. More interns believed that primary care may be effectively delivered via video visits compared with phone visits (77% vs. 35%). Most interns (69%) missed clinical time during medical school due to the COVID-19 pandemic; 41% felt that the pandemic negatively affected their ambulatory care preparation. Overall, the majority of interns (58%) felt prepared for primary care; only 12% felt prepared to deliver primary care using either video or phone visits. Conclusions: Although IM interns had favorable attitudes toward video and phone visits, few had training or clinical experience; most felt unprepared. Residency programs may need to close training gaps for current interns in conducting telehealth video and phone visits.

Targeted inhibition of BRAF V600E achieves tumor control in a subset of advanced thyroid tumors. Nearly all tumors develop resistance, and some have been observed to subsequently undergo dedifferentiation. The molecular alterations associated with thyroid cancer dedifferentiation in the setting of BRAF inhibition are unknown. We analyzed targeted next-generation sequencing data from 639 advanced, recurrent and/or metastatic thyroid carcinomas, including 15 tumors that were treated with BRAF inhibitor drugs and had tissue sampled during or posttreatment, 8 of which had matched pretherapy samples. Pre- and posttherapy tissues from one additional patient were profiled with whole-exome sequencing and RNA expression profiling. Mutations in genes comprising the SWI/SNF chromatin remodeling complex and the PI3K–AKT–mTOR, MAPK, and JAK–STAT pathways all increased in prevalence across more dedifferentiated thyroid cancer histologies. Of 7 thyroid cancers that dedifferentiated after BRAF inhibition, 6 had mutations in these pathways. These mutations were mostly absent from matched pretreatment samples and were rarely detected in tumors that did not dedifferentiate. Additional analyses in one of the vemurafenib-treated tumors before and after anaplastic transformation revealed the emergence of an oncogenic PIK3CA mutation, activation of ERK signaling, dedifferentiation, and development of an immunosuppressive tumor microenvironment. These findings validate earlier preclinical data implicating these genetic pathways in resistance to BRAF inhibitors, and suggest that genetic alterations mediating acquired drug resistance may also promote thyroid tumor dedifferentiation. Implications: The possibility that thyroid cancer dedifferentiation may be attributed to selective pressure applied by BRAF inhibitor–targeted therapy should be investigated further.

The aim of this study was to demonstrate that uveal melanoma (UM) treated with eye plaque brachytherapy (EPB) with intra-operative ultrasound (IOUS) guidance results in increased local control.A retrospective study was conducted among 212 patients with 214 UM tumors treated by iodine-125 EPB with IOUS guidance from 2013 to 2019. 85 Gy was prescribed to tumor apical height or 5 mm from inner sclera, whichever was greater. Lesions were treated to 95% of 85 Gy at 2 mm margin from tumor edge. Local failure (LF), distant metastasis (DM), and radiation-related toxicity were recorded.Median tumor apical height was 3.3 mm. COMS stage was 90 small (42.1%), 81 medium (37.9%), and 43 large (20.1%). Most patients had gene expression profile (GEP) class available, with 119 (55.6%), 30 (14.0%), 55 (25.7%) cases classified as 1A, 1B, and 2, respectively. Median dose at apex for tumor height5 mm and ≤ 5 mm was 85.0 Gy and 120.6 Gy, respectively. Outcomes data for 180 patients with over 12 months follow-up were reported. Mean follow-up was 37.3 months. Rates of LF and DM were 0.0% and 12.2%, respectively. Actuarial estimates of 5-year DM for class 1A, 1B, and 2 tumors were 2.5%, 0.0%, and 57.8%, respectively. 87 patients (48.3%) developed radiation-related toxicities.The excellent local control rate amongst lesions ranging across all sizes and GEP classes emphasizes the importance of image-guided brachytherapy with IOUS. We report favorable 5-year DM rates compared to established rates. Acceptable rate and severity of radiation-related toxicities were observed.

Nerve mediated inflammatory monocyte recruitment in perineural invasion.

Supplementary Data: Tables S1-S2; Figures S1-S4

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC.Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review.Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC.Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805–15. ©2018 AACR.

Figure S12

Table S1- Tumor response by RECIST criteria. Table S2- Treatment details and reasons for discontinuation.

Expanded methods for the study.

Treatment-Related Adverse Events Occurring in {greater than or equal to}1 Patient Treated With Pembrolizumab plus Ipilimumab

This is the legend for the supplemental figure

Purpose:To determine whether SD-101, a Toll-like receptor 9 agonist, potentiates the antitumor activity of anti-PD-1 antibodies in patients with anti-PD-1/PD-L1 naïve, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC).Patients and Methods:Patients with PD-1 Ab-naïve HNSCC received either 2 mg SD-101 injected in one to four lesions or 8 mg SD-101 injected into a single lesion weekly × 4 doses then every 3 weeks × 7 doses. Pembrolizumab was administered at 200 mg every 3 weeks.Results:A total of 28 patients received 2 mg and 23 received 8 mg per injection, respectively. A total of 76% of patients had received prior systemic therapy. Combined positive score was ≥1 to < 20 in 35 patients (70%) and ≥ 20 in 15 patients (30%) of 50 patients with available data. There were 12 patients with grade ≥3 treatment-related adverse events (24%), and no treatment-related deaths. The objective response rate was 24% including 2 complete and 10 partial responses. The median duration of response was 7.0 [95% confidence interval (CI): 2.1–11.1] months. The response rate was higher in human papillomavirus–positive (HPV+) patients (44%, N = 16). Responses were not associated with PD-L1 expression levels or IFNγ-related gene expression at baseline. Responses were observed both in injected (32%) and in noninjected lesions (29%). Progression-free and overall survival at 9 months were 19.0% (95% CI: 9.1–31.7) and 64.7% (95% CI: 45.3–78.7), respectively.Conclusions:SD-101 combined with pembrolizumab induced objective responses, especially in HPV+ tumors, which were frequently associated with increased intratumoral inflammation and effector immune cell activity.

Purpose:Previous studies indicate that the benefit of therapy depends on patients' risk for cancer recurrence relative to noncancer mortality (ω ratio). We sought to test the hypothesis that patients with head and neck cancer (HNC) with a higher ω ratio selectively benefit from intensive therapy.Experimental Design:We analyzed 2,688 patients with stage III–IVB HNC undergoing primary radiotherapy (RT) with or without systemic therapy on three phase III trials (RTOG 9003, RTOG 0129, and RTOG 0522). We used generalized competing event regression to stratify patients according to ω ratio and compared the effectiveness of intensive therapy as a function of predicted ω ratio (i.e., ω score). Intensive therapy was defined as treatment on an experimental arm with altered fractionation and/or multiagent concurrent systemic therapy. A nomogram was developed to predict patients' ω score on the basis of tumor, demographic, and health factors. Analysis was by intention to treat.Results:Decreasing age, improved performance status, higher body mass index, node-positive status, P16-negative status, and oral cavity primary predicted a higher ω ratio. Patients with ω score ≥0.80 were more likely to benefit from intensive treatment [5-year overall survival (OS), 70.0% vs. 56.6%; HR of 0.73, 95% confidence interval (CI): 0.57–0.94; P = 0.016] than those with ω score P = 0.69; P = 0.019 for interaction). In contrast, the effectiveness of intensive therapy did not depend on risk of progression.Conclusions:Patients with HNC with a higher ω score selectively benefit from intensive treatment. A nomogram was developed to help select patients for intensive therapy.

Tables contain information on the list of candidate genes screened from murine macrophages and clinical data on human pancreatic samples. This file contains 2 tables (Supplemental Tables 1 and 2).

Supplementary figure and table legends

Detailed genetic results

Analysis of human prostate cancer and adenoid cystic carcinoma specimens demonstrates macrophage infiltration around the majority of invaded nerves. This file contains two supplemental figures (S10-S11).

Photomicrographs of two ETV6-NTRK3 fusion cases.

Table S3

Purpose:Salivary gland carcinomas (SGC) are rare, aggressive cancers with high rates of recurrence and distant metastasis. These factors, and a lack of active systemic therapies, contribute to poor clinical outcome. Response rates with immune checkpoint blockade have been low, although clinical data remain sparse. To improve the efficacy of therapies, a more comprehensive understanding of relevant molecular alterations and immunologic processes is needed.Experimental Design:To characterize the immune microenvironment and neoantigen landscape of SGCs, we performed RNA sequencing (RNA-seq) in 76 tumors representing the three most lethal histologies: adenoid cystic carcinoma (ACC), myoepithelial carcinoma (MECA), and salivary duct carcinoma (SDC). We analyzed transcriptomic profiles, tumor-infiltrating immune cell populations, and measures of T-cell activation/dysfunction. In 37 cases also undergoing exome sequencing, we analyzed somatic mutations and neoantigens.Results:SDCs exhibited high levels of immune infiltration, with corresponding higher levels of T-cell dysfunction, and higher mutational load. In contrast, ACCs were characterized by an immune-excluded microenvironment, the presence of M2-polarized macrophages and myeloid-derived suppressor cells, and very low mutational load. MECAs were more heterogeneous, with both immune-low and immune-high phenotypes represented. Across all SGCs, levels of immune infiltration were associated with mutation- and fusion-derived neoantigens, and with aggressive clinical behavior.Conclusions:These findings provide new insights into the immune microenvironment and neoantigen landscape of SGCs, showing that mechanisms of immune escape appear to differ by histology. These data nominate potential immunologic vulnerabilities and may help guide the next steps of investigation in precision immunotherapy for these difficult-to-treat cancers.

Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI, but the contributing conditions within the tumor microenvironment are not well understood. Here, we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B–mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2–CCR2 signaling or cathepsin B function significantly impaired PNI in vivo. Correlative studies in human specimens demonstrated that cathepsin B–producing macrophages were enriched in invaded nerves, which was associated with increased local tumor recurrence. These findings deepen our understanding of PNI pathogenesis and illuminate how PNI is driven in part by corruption of a nerve repair program. Further, they support the exploration of inhibiting IM recruitment and function as a targeted therapy for PNI. Cancer Res; 77(22); 6400–14. ©2017 AACR.

Supplementary Figure from Intralesional SD-101 in Combination with Pembrolizumab in Anti-PD-1 Treatment-Naïve Head and Neck Squamous Cell Carcinoma: Results from a Multicenter, Phase II Trial

Purpose:Interferon-α favors a Th1 shift in immunity, and combining with ipilimumab (ipi) at 3 or 10 mg/kg may downregulate CTLA4-mediated suppressive effects, leading to more durable antitumor immune responses. A study of tremelimumab and high-dose interferon-α (HDI) showed promising efficacy, supporting this hypothesis.Patients and Methods:E3611 followed a 2-by-2 factorial design (A: ipi10+HDI; B: ipi10; C: ipi3+HDI; D: ipi3) to evaluate (i) no HDI versus HDI (across ipilimumab doses) and (ii) ipi3 versus ipi10 (across HDI status). We hypothesized that median progression-free survival (PFS) would improve from 3 to 6 months with HDI versus no HDI and with ipi10 versus ipi3.Results:For eligible and treated patients (N = 81) at a median follow-up time of 29.8 months, median PFS was 4.4 months [95% confidence interval (CI), 2.7–8.2] when ipilimumab was used alone and 7.5 months (95% CI, 5.1–11.0) when HDI was added. Median PFS was 3.8 months (95% CI, 2.6–7.5) with 3 mg/kg ipilimumab and 6.5 months (95% CI, 5.1–13.5) with 10 mg/kg. By study arm, median PFS was 8.0 months (95% CI, 2.8–20.2) in arm A, 6.2 months (95% CI, 2.7–25.7) in B, 5.7 months (95% CI, 1.5–11.1) in C, and 2.8 months (95% CI, 2.6–5.7) in D. The differences in PFS and overall survival (OS) did not reach statistical significance. Adverse events were consistent with the known profiles of ipilimumab and HDI and significantly higher with HDI and ipi10.Conclusions:Although PFS was increased, the differences resulting from adding interferon-α or a higher dose of ipilimumab did not reach statistical significance and do not outweigh the added toxicity risks.

Purpose: We sought to identify genomic alterations (GA) in salivary gland adenocarcinomas, not otherwise specified (NOS), salivary duct carcinomas (SDC), carcinoma ex pleomorphic adenoma (ca ex PA), and salivary carcinoma, NOS.Experimental Design: DNA was extracted from 149 tumors. Comprehensive genomic profiling (CGP) was performed on hybridization-captured adaptor ligation-based libraries of 182 or 315 cancer-related genes plus introns from 14 or 28 genes frequently rearranged for cancer and evaluated for all classes of GAs.Results: A total of 590 GAs were found in 157 unique genes (mean 3.9/tumor). GAs in the PI3K/AKT/mTOR pathway were more common in SDC (53.6%) than other histologies (P = 0.019) Cyclin-dependent kinase GAs varied among all histotypes: adenocarcinoma, NOS (34.6%); SDC (12.2%); ca ex PA (16.7%); carcinoma, NOS (31.2%; P = 0.043). RAS GAs were observed: adenocarcinoma, NOS (17.3%); SDC (26.8%); ca ex PA (4.2%); and carcinoma, NOS (9.4%; P = 0.054). ERBB2 GAs, including amplifications and mutations, were common: adenocarcinoma, NOS (13.5%); SDC (26.8%); ca ex PA (29.2%); carcinoma, NOS (18.8; P = 0.249). Other notable GAs include TP53 in >45% of each histotype; NOTCH1: adenocarcinoma, NOS (7.7%), ca ex PA (8.3%), carcinoma, NOS (21.6%); NF1: adenocarcinoma, NOS (9.6%), SDC (17.1%), carcinoma, NOS (18.8%). RET fusions were identified in one adenocarcinoma, NOS (CCDC6-RET) and two SDCs (NCOA4-RET). Clinical responses were observed in patients treated with anti-HER2 and anti-RET–targeted therapies.Conclusions: CGP of salivary adenocarcinoma, NOS, SDCs, ca ex PA, and carcinoma, NOS revealed diverse GAs that may lead to novel treatment options. Clin Cancer Res; 22(24); 6061–8. ©2016 AACR.

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