Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

The scarcity of malignant Hodgkin and Reed-Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels1-4. Here we show that the plasma representation of mutations exceeds the bulk tumour representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumours, we demonstrate Hodgkin and Reed-Sternberg ctDNA shedding to be shaped by DNASE1L3, whose increased tumour microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R mutations that are dependent on IL-13 signalling and therapeutically targetable with IL-4Rα-blocking antibodies. Finally, using PhasED-seq5, we demonstrate the clinical value of pretreatment and on-treatment ctDNA levels for longitudinally refining cHL risk prediction and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL, as well as capturing molecularly distinct subtypes with diagnostic, prognostic and therapeutic potential.

Measurable residual disease conversion rate with consolidation chemotherapy in acute myeloid leukemia.

The rate of MRD clearance in AML with standard consolidation chemotherapy is not well defined. A multi-institution retrospective analysis was performed on 107 consecutively treated AML patients in morphologic complete remission with detectable MRD post-induction therapy who received standard chemotherapy consolidation. In response to standard intermediate/high-dose cytarabine consolidation therapy, 26 of 60 patients (43.3%) with MRD threshold of detection of at least 0.1% converted to MRD-negative status (undetectable with assay used), and 6 of 47 patients (12.8%) with MRD threshold of detection > 0.1% converted to MRD-negative status. Multivariable logistic regression for patients with MRD threshold of detection of at least 0.1% showed that, when controlling for age, ELN risk category, dose of cytarabine, and use of a combination agent, treatment with 1 cycle of consolidation cytarabine versus ≥2 cycles decreased the odds of conversion of AML to MRD-negative (OR = 0.24, 95% CI 0.07-0.85, p = 0.03).

Functional screening of amplification outlier oncogenes in organoid models of early tumorigenesis.

Somatic copy number gains are pervasive across cancer types, yet their roles in oncogenesis are insufficiently evaluated. This inadequacy is partly due to copy gains spanning large chromosomal regions, obscuring causal loci. Here, we employed organoid modeling to evaluate candidate oncogenic loci identified via integrative computational analysis of extreme copy gains overlapping with extreme expression dysregulation in The Cancer Genome Atlas. Subsets of "outlier" candidates were contextually screened as tissue-specific cDNA lentiviral libraries within cognate esophagus, oral cavity, colon, stomach, pancreas, and lung organoids bearing initial oncogenic mutations. Iterative analysis nominated the kinase DYRK2 at 12q15 as an amplified head and neck squamous carcinoma oncogene in p53-/- oral mucosal organoids. Similarly, FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, promoted p53-/- esophageal organoid growth reversible by small molecule and soluble receptor antagonism of FGFRs. Our studies establish organoid-based contextual screening of candidate genomic drivers, enabling functional evaluation during early tumorigenesis.

Efficacy of checkpoint inhibition after CAR-T failure in aggressive B-cell lymphomas: outcomes from 15 US institutions.

Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes.

Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.

Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

The Cup Runneth Over: Treatment Strategies for Newly Diagnosed Acute Myeloid Leukemia.

Since 2017, the number of agents for acute myeloid leukemia (AML) has rapidly expanded. Given the increased therapeutic options, better identification of high-risk subsets of AML and more refined approaches to patient fitness assessment, the decisions surrounding selection of intensive chemotherapy versus lower-intensity treatment have grown increasingly more nuanced. In this review, we present available data for both standard and investigational approaches in the initial treatment of AML using an intensive chemotherapy backbone or a lower-intensity approach. We summarize management strategies in newly diagnosed secondary AML, considerations around allogeneic stem-cell transplantation, and the role of maintenance therapy. Finally, we highlight important areas of future investigation and novel agents that may hold promise in combination with standard therapies.

Metastatic Parotid Gland Carcinoma With ERBB2 Amplification With Complete Response to Fam-Trastuzumab Deruxtecan.

HER2 mutations have been shown to be targetable in select cases of salivary gland cancers with overexpression or amplification of the HER2 oncogene. Fam-trastuzumab deruxtecan, a novel antibody-drug conjugate that combines trastuzumab with a topoisomerase I inhibitor, has recently demonstrated efficacy as a third-line agent in HER2-overexpressing breast cancer after trastuzumab failure. These promising results in breast cancer suggest a potential paradigm for use in other tumors with known HER2 alterations, including salivary gland cancer. This report describes a 67-year-old man with HER2-positive metastatic parotid gland carcinoma who experienced disease progression after parotidectomy with adjuvant cisplatin-based chemoradiation, neratinib, and ado-trastuzumab emtansine. After disease progression on the latter HER2-directed therapy, his malignancy demonstrated complete response to fam-trastuzumab deruxtecan, which has been sustained for the past 7 months. Fam-trastuzumab deruxtecan appears to be a well-tolerated therapeutic option in patients with HER2-positive salivary gland carcinoma, with activity demonstrated after progression on ado-trastuzumab emtansine and HER2-directed kinase inhibition. Further studies should be conducted to explore the use of this agent in HER2-positive salivary gland cancers.

The role of insurance status as a mediator of racial disparities in oropharyngeal cancer outcomes.

BACKGROUND: To assess the role of insurance status as a mediator of racial disparities in oropharyngeal cancer outcomes. METHODS: This was a population-based retrospective cohort study. Data were extracted from the Surveillance, Epidemiology, and End Results 18 database. The study cohort included 11 627 patients diagnosed with oropharyngeal squamous cell carcinoma between 2010 and 2015. RESULTS: The association between black race and increased risk of unresectable disease was slightly attenuated, but persistent, after including insurance status as a covariate (odds ratio [OR] 1.34, 95%CI 1.10-1.63). Likewise, black race was no longer associated with worse disease-specific survival (hazard ratio [HR] 1.11, 95%CI 0.99-1.26), but remained associated with worse overall survival with a slightly decreased effect size (HR 1.13, 95%CI 1.01-1.25). CONCLUSIONS: Insurance status plays a significant role in, but does not completely account for, the persistent racial disparities in oropharyngeal cancer outcomes.

Association Between Age and Nodal Metastasis in Papillary Thyroid Carcinoma.

OBJECTIVE: To determine the relationship between age and rate of lymph node metastasis, nodal burden of disease, as well as rate of lateral neck disease in papillary thyroid cancer, especially in patients aged <30 years. STUDY DESIGN: Population-based cross-sectional study. SETTING: Population-based cancer database. METHODS: Data were extracted from the SEER 18 database (Surveillance, Epidemiology, and End Results) of the National Cancer Institute. The study cohort included 59,330 patients diagnosed with papillary thyroid cancer between 1988 and 2015. Patients aged 0 to 10 years, 11 to 20 years, and 21 to 30 years old were compared with those >30 years. All analyses were adjusted for sex, race, and T classification. RESULTS: The overall rate of lymph node metastasis was 26.11%, which increased with decreasing age. Adjusted odds ratios of lymph node metastasis were 7.19 (95% CI, 3.76-13.75) for the 0- to 10-year-old group, 3.45 (95% CI, 3.08-3.87) for the 11- to 20-year-old group, and 2.28 (95% CI, 2.15-2.41) for the 21- to 30-year-old group, relative to the group >30 years old. Decreased age was also associated with increased total positive nodes, increased lymph node ratio, and increased risk of lateral neck disease. CONCLUSION: Pediatric and early young adult patients with papillary thyroid carcinoma have a greater risk of lymph node metastasis, greater burden of nodal disease, and a greater risk of lateral neck metastases.

Functional Outcomes of Septal Extension Grafting in Aesthetic Rhinoplasty: A Cohort Analysis.

Background: Septal extension grafts (SEGs) are used widely in rhinoplasty as a means of controlling tip position. Grafts positioned in a side-to-side configuration may cause nasal airway obstruction. Methods: Retrospective cohort analysis of patients undergoing cosmetic rhinoplasty. Patients undergoing SEG placement were grouped according to completion of the Nasal Obstruction Symptom Evaluation (NOSE) or Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS). The latter has a cosmetic (C) and functional (O) domain. Each group was matched to a cohort that did not undergo SEG placement using criteria: preoperative NOSE or SCHNOS-O score, age, and gender. Patient demographics and outcomes, including NOSE, SCHNOS, and visual analog scale (VAS) scores, were compared between SEG and no-SEG groups using univariate and multivariate analyses. If patients underwent placement of an SEG and complained of obstruction, the laterality of the graft in relation to the complaint was examined. Results: SEGs were placed in 79 patients, of whom 77 completed the NOSE survey and 37 completed the SCHNOS-O both pre- and postoperatively. These patients were matched to patients without SEGs. For both the SCHNOS and NOSE-matched cohorts, functional outcomes (NOSE, SCHNOS-O, and VAS-F) did not significantly differ between SEG and no-SEG groups. These findings were also observed when patients were stratified by cosmetic surgery alone versus combined functional and cosmetic surgery. On multivariate linear regression analysis, when accounting for intraoperative techniques, there was no difference in postoperative NOSE or SCHNOS-O outcomes between the SEG and no-SEG cohorts. Side of postoperative nasal obstruction did not correlate with side of SEG placement. Conclusion: SEGs, when used in a unilateral side-to-side configuration, yield excellent aesthetic results without compromising functional outcomes.

Universal Screening of Gastrointestinal Malignancies for Mismatch Repair Deficiency at Stanford.

BACKGROUND: In light of recent Food and Drug Administration (FDA) approval of immune checkpoint inhibitors for mismatch repair deficient (dMMR) malignancies, identifying patients with dMMR malignancies has become increasingly important. Although screening for dMMR in colorectal cancer (CRC) is recommended, it is less common for extracolonic gastrointestinal (GI) malignancies. At Stanford Comprehensive Cancer Institute (SCCI), all GI malignancies have been screened for dMMR via immunohistochemistry since January 2016. METHODS: In this study, we conducted a retrospective review of all patients with GI malignancies screened for dMMR between January 2016 and December 2017. Tumor sequencing was performed on cases negative for germline pathogenic variants where tumor material was available. RESULTS: A total of 1425 consecutive GI malignancies were screened for dMMR at SCCI during the study period, and 1374 were included for analysis. dMMR was detected in 7.2% of all GI malignancies. We detected the highest prevalence of dMMR in gastric (15 of 150, 10.0%) followed by colorectal (63 of 694, 9.1%), pancreatic (13 of 244, 5.3%), and gastroesophageal malignancy (6 of 132, 4.5%) patients. Lynch syndrome was the most common etiology for dMMR in colorectal cancer (41.5%), double somatic (confirmed or possible) pathogenic variants the most common etiology in pancreatic cancer (44.4%), and somatic MLH1 hypermethylation the most common etiology in gastric (73.3%) and gastroesophageal cancer (83.3%). CONCLUSIONS: Given the relatively high incidence of dMMR in GI malignancies, we recommend screening all GI malignancies. Our results suggest that although a rare occurrence, double somatic pathogenic variants may be a biologically significant pathway causing dMMR in pancreatic cancer.

Update on International Cooperative Groups Studies in Thoracic Malignancies: The Emergence of Immunotherapy.

Cancer cooperative groups have historically played a critical role in the advancement of non-small-cell lung cancer therapy. Representatives from cooperative groups worldwide convene at the International Lung Cancer Congress annually. The International Lung Cancer Congress had its 17th anniversary in the summer of 2016. The present review highlights the thoracic malignancy studies discussed by presenters. The included studies are merely a sample of the trials of thoracic malignancies ongoing globally.

Laser interstitial thermal therapy for the treatment of epilepsy: evidence to date.

Medically intractable epilepsy is associated with increased morbidity and mortality. For those with focal epilepsy and correlated electrophysiological or radiographic features, open surgical resection can achieve high rates of seizure control, but can be associated with neurologic deficits and cognitive effects. Recent innovations have allowed for more minimally invasive methods of surgical seizure control such as magnetic resonance-guided laser interstitial therapy (MRgLITT). MRgLITT achieves the goal of ablating seizure foci while preserving neuropsycho-logical function and offering real-time feedback and monitoring of tissue ablation. This review summarizes the utilization of MRgLITT for mesial temporal lobe epilepsy and other seizure disorders. Overall, the efficacy of MRgLITT is comparable to that of open surgery and offers a less invasive approach in patients with significantly less morbidity.

Nectin-1-specific entry of herpes simplex virus 1 is sufficient for infection of the cornea and viral spread to the trigeminal ganglia.

PURPOSE: Primary and recurrent infections of the cornea by herpes simplex virus 1 (HSV-1) are important causes of eye disease. Three unrelated classes of glycoprotein D receptors for HSV-1 entry into cells have been identified. This study was undertaken to uncover the relative significance of nectin-1 as an entry receptor in corneal infection and HSV-1 spread to the trigeminal ganglia (TG), a site important for HSV-1 latency and recurrent corneal infection. METHODS: To assess the significance of nectin-1, a member of the immunoglobulin superfamily, in primary HSV-1 infection and spread to the TG, we used a murine model of corneal infection and a HSV-1 mutant, KOS(Rid1), which can only use nectin-1 for entry. Immunohistochemistry, real-time PCR, and plaque assays using HSV-1 infected tissues were performed. RESULTS: We demonstrated that receptor usage by HSV-1 limited to nectin-1 does not significantly change the spread of HSV-1 in the corneal epithelium during primary infection. We also found that nectin-1-specific entry does not affect the capacity of the virus to spread to the TG from the cornea. CONCLUSIONS: Our findings suggest that nectin-1 alone is sufficient for HSV-1 entry into the cornea and spread to the TG.