Sex-specific mating pheromones in the nematode Panagrellus redivivus

Nematodes use an extensive chemical language based on glycosides of the dideoxysugar ascarylose for developmental regulation (dauer formation), male sex attraction, aggregation, and dispersal. However, no examples of a female- or hermaphrodite-specific sex attractant have been identified to date. In this study, we investigated the pheromone system of the gonochoristic sour paste nematode Panagrellus redivivus, which produces sex-specific attractants of the opposite sex. Activity-guided fractionation of the P. redivivus exometabolome revealed that males are strongly attracted to ascr#1 (also known as daumone), an ascaroside previously identified from Caenorhabditis elegans hermaphrodites. Female P. redivivus are repelled by high concentrations of ascr#1 but are specifically attracted to a previously unknown ascaroside that we named dhas#18, a dihydroxy derivative of the known ascr#18 and an ascaroside that features extensive functionalization of the lipid-derived side chain. Targeted profiling of the P. redivivus exometabolome revealed several additional ascarosides that did not induce strong chemotaxis. We show that P. redivivus females, but not males, produce the male-attracting ascr#1, whereas males, but not females, produce the female-attracting dhas#18. These results show that ascaroside biosynthesis in P. redivivus is highly sex-specific. Furthermore, the extensive side chain functionalization in dhas#18, which is reminiscent of polyketide-derived natural products, indicates unanticipated biosynthetic capabilities in nematodes

ERBB family fusions are recurrent and actionable oncogenic targets across cancer types

PurposeGene fusions involving receptor tyrosine kinases (RTKs) define an important class of genomic alterations with many successful targeted therapies now approved for ALK, ROS1, RET and NTRK gene fusions. Fusions involving the ERBB family of RTKs have been sporadically reported, but their frequency has not yet been comprehensively analyzed and functional characterization is lacking on many types of ERBB fusions.Materials and methodsWe analyzed tumor samples submitted to Caris Life Sciences (n=64,354), as well as the TCGA (n=10,967), MSK IMPACT (n=10,945) and AACR GENIE (n=96,324) databases for evidence of EGFR, ERBB2 and ERBB4 gene fusions. We also expressed several novel fusions in cancer cell lines and analyzed their response to EGFR and HER2 tyrosine kinase inhibitors (TKIs).ResultsIn total, we identified 1,251 ERBB family fusions, representing an incidence of approximately 0.7% across all cancer types. EGFR, ERBB2, and ERBB4 fusions were most frequently found in glioblastoma, breast cancer and ovarian cancer, respectively. We modeled two novel types of EGFR and ERBB2 fusions, one with a tethered kinase domain and the other with a tethered adapter protein. Specifically, we expressed EGFR-ERBB4, EGFR-SHC1, ERBB2-GRB7 and ERBB2-SHC1, in cancer cell lines and demonstrated that they are oncogenic, regulate downstream signaling and are sensitive to small molecule inhibition with EGFR and HER2 TKIs.ConclusionsWe found that ERBB fusions are recurrent mutations that occur across multiple cancer types. We also establish that adapter-tethered and kinase-tethered fusions are oncogenic and can be inhibited with EGFR or HER2 inhibitors. We further propose a nomenclature system to categorize these fusions into several functional classes

Immune-related (IR)-pneumonitis during the COVID-19 pandemic: multidisciplinary recommendations for diagnosis and management

Immune-related (IR)-pneumonitis is a rare and potentially fatal toxicity of anti-PD(L)1 immunotherapy. Expert guidelines for the diagnosis and management of IR-pneumonitis include multidisciplinary input from medical oncology, pulmonary medicine, infectious disease, and radiology specialists. Severe acute respiratory syndrome coronavirus 2 is a recently recognized respiratory virus that is responsible for causing the COVID-19 global pandemic. Symptoms and imaging findings from IR-pneumonitis and COVID-19 pneumonia can be similar, and early COVID-19 viral testing may yield false negative results, complicating the diagnosis and management of both entities. Herein, we present a set of multidisciplinary consensus recommendations for the diagnosis and management of IR-pneumonitis in the setting of COVID-19 including: (1) isolation procedures, (2) recommended imaging and interpretation, (3) adaptations to invasive testing, (4) adaptations to the management of IR-pneumonitis, (5) immunosuppression for steroid-refractory IR-pneumonitis, and (6) management of suspected concurrent IR-pneumonitis and COVID-19 infection. There is an emerging need for the adaptation of expert guidelines for IR-pneumonitis in the setting of the global COVID-19 pandemic. We propose a multidisciplinary consensus on this topic, in this position paper

Current approaches to neoadjuvant immunotherapy in resectable non-small cell lung cancer

Purpose of review: For decades, early-stage resectable non-small cell lung cancer (NSCLC), while potentially curable, has been marred by unacceptably high recurrence rates. Recent findings: Anti-PD(L)1 immune checkpoint blockade (ICB) has revolutionized the treatment of advanced NSCLC, and with recent approvals in the peri-operative space, is now poised to transform the systemic treatment paradigm for localized and locally-advanced NSCLC. In this review, we focus on neoadjuvant ICB in resectable NSCLC, highlighting the pre-clinical rationale for neoadjuvant ICB, early clinical trials, randomized phase 3 trial data, and future directions for resectable NSCLC.</p

EML4-ALK Rearrangement as a Mechanism of Resistance to Osimertinib in Metastatic Lung Adenocarcinoma: A Case Report

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is the preferred frontline therapy for EGFR-mutant advanced NSCLC. However, despite its high initial response rates, multiple EGFR-independent mechanisms of resistance have been reported in patients receiving osimertinib. One such mechanism is the emergence of acquired, targetable oncogenic fusion events. It has been documented in other case reports that combination therapies can be efficacious in these scenarios. In our case report, we present a patient with EGFR-mutant advanced NSCLC who developed an acquired EML4-ALK rearrangement mediating resistance to osimertinib, which was overcome by using a combination of osimertinib with the ALK tyrosine kinase inhibitor alectinib

Infectious complications in patients with non-small cell lung cancer treated with immune checkpoint inhibitors

Introduction: Immune checkpoint inhibitors (ICI) are standard treatment for nonsmall cell lung cancer (NSCLC). However, the burden of infectious complications during ICI therapy is poorly described. Materials and methods: We conducted a retrospective study of patients with NSCLC treated with ICIs between 2007 and 2020 at a tertiary academic center. The incidence, characteristics, and healthcare utilization outcomes of infections during ICI therapy and within 3 months of ICI discontinuation are presented using descriptive statistics. Cox proportional hazard models are used to examine infection-free survival by demographic and treatment factors. Associations between patient or treatment characteristics and hospitalization or ICU admission are analyzed by logistic regression, presented as odds ratios (OR). Results: Of 298 patients, infections occurred in 54.4% (n = 162). Of these patients, 59.3% (n = 96) required hospitalization and 15.4% (n = 25) required ICU admission. The most common infection was bacterial pneumonia. Fungal infections occurred in 12 patients (7.4%). Patients with chronic obstructive pulmonary disease (COPD) (OR 2.15, 95% CI, 1.01-4.58), corticosteroid treatment within 1 month prior to infection onset (OR 3.04, 95% CI, 1.47-6.30), and concomitant irAE and infection (OR 5.48, 95% CI, 2.15-14.00) had higher odds of hospitalization. Corticosteroid use was associated with higher odds of ICU admission (OR 3.09, 95% CI, 1.29-7.38). Conclusion: In this large single-institution study we identify that more than half of patients with ICI-treated NSCLC develop infectious complications. We identify that patients with COPD, recent corticosteroid use, and concomitant irAE and infection have higher odds of hospitalization, and that unusual infections (eg, fungal) can occur. This highlights clinical awareness of infections as important complications during ICI therapy in patients with NSCLC.</p

Infectious complications in patients with non-small cell lung cancer treated with immune checkpoint inhibitors

Introduction: Immune checkpoint inhibitors (ICI) are standard treatment for nonsmall cell lung cancer (NSCLC). However, the burden of infectious complications during ICI therapy is poorly described. Materials and methods: We conducted a retrospective study of patients with NSCLC treated with ICIs between 2007 and 2020 at a tertiary academic center. The incidence, characteristics, and healthcare utilization outcomes of infections during ICI therapy and within 3 months of ICI discontinuation are presented using descriptive statistics. Cox proportional hazard models are used to examine infection-free survival by demographic and treatment factors. Associations between patient or treatment characteristics and hospitalization or ICU admission are analyzed by logistic regression, presented as odds ratios (OR). Results: Of 298 patients, infections occurred in 54.4% (n = 162). Of these patients, 59.3% (n = 96) required hospitalization and 15.4% (n = 25) required ICU admission. The most common infection was bacterial pneumonia. Fungal infections occurred in 12 patients (7.4%). Patients with chronic obstructive pulmonary disease (COPD) (OR 2.15, 95% CI, 1.01-4.58), corticosteroid treatment within 1 month prior to infection onset (OR 3.04, 95% CI, 1.47-6.30), and concomitant irAE and infection (OR 5.48, 95% CI, 2.15-14.00) had higher odds of hospitalization. Corticosteroid use was associated with higher odds of ICU admission (OR 3.09, 95% CI, 1.29-7.38). Conclusion: In this large single-institution study we identify that more than half of patients with ICI-treated NSCLC develop infectious complications. We identify that patients with COPD, recent corticosteroid use, and concomitant irAE and infection have higher odds of hospitalization, and that unusual infections (eg, fungal) can occur. This highlights clinical awareness of infections as important complications during ICI therapy in patients with NSCLC.</p

Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer

Background We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab.Methods Patients with resectable stage IB (≥4 cm)–IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint.Results While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations.Conclusions Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response