Brief Report: Second-line treatment outcomes in patients with advanced NSCLC previously treated with first-line immunotherapy regimens.

CLINICAL PRACTICE POINTS: In the United States of America, nearly all patients with advanced NSCLC, absent oncogenic drivers, receive some form of immunotherapy (IO) as part of initial treatment. Current national guidelines currently recommend against IO re-challenge if there is disease progression on IO in the first line, but re-treatment with IO is attractive given its favorable toxicity profile and descriptions of durable clinical benefit in a subset of patients treated beyond disease progression on initial IO (Gandara, J Thorac Oncol, 2018). Data in the non-clinical trial setting on the efficacy of IO in sequential lines of treatment after initial IO are lacking. In our large cohort study of patients with advanced NSCLC treated with immunotherapy regimens in the first-line setting, we find that outcomes after second-line treatment did not differ statistically by type of treatment used in the second line. While current prospective clinical trials are investigating several aspects of the utility of continuing immunotherapy and adding novel agents, our study offers data outside of a clinical trial. In addition, with the increased prevalence of adjuvant immunotherapy we urgently need to wrestle with whether to continue immunotherapy in the first-line metastatic setting if a patient experiences disease progression on adjuvant immunotherapy. While this analysis does not directly investigate that question, it does provide hypothesis-generating evidence for further evaluations.

Radiographic and Clinical Evidence for Osteoarthritis at Medium-Term Follow-up after Arthroscopic Partial Medial Meniscectomy.

OBJECTIVE: The purpose of this study is to assess if incident radiographic osteoarthritis (OA) is associated with clinical OA symptoms at midterm follow-up after arthroscopic partial medial meniscectomy (APMM). DESIGN: A total of 44 patients (43% females, mean age 50.1 ± 2.8 years, minimum 5.6-year follow-up) with isolated medial meniscal tears and no-to-mild preoperative radiographic OA underwent APMM. Incident radiographic OA was assessed using the modified Kellgren-Lawrence (K-L) classification. Patients completed the Knee Injury and Osteoarthritis Outcomes Score (KOOS), and subscale thresholds for assessment of a symptomatic knee (KOOS OA criteria) and for Patient non-Acceptable Symptom State (PASS-N) following anterior cruciate ligament reconstruction (ACL-R) were calculated. RESULTS: Incident medial compartment OA occurred in 50% of patients. Morbidly obese patients (body mass index ≥35 kg/m2) were more likely to demonstrate incident radiographic OA (100% vs. 41%, P = 0.002). Forty-three percent of patients met KOOS OA criteria, while 77% were PASS-N. Females were more likely to meet KOOS OA criteria (73% vs. 21%, P = 0.009). Patients with incident radiographic OA in any compartment were more likely than those without radiographic OA to meet KOOS OA criteria (71% vs. 17%, P = 0.008). Patients with preoperative K-L grade 2 changes in any compartment were more likely to meet KOOS OA criteria than those without K-L grade 2 changes in any compartment (83% vs. 35%, P = 0.037). CONCLUSIONS: Roughly half of APMM patients will have incident radiographic OA within 6 years of APMM, and this risk increases with obesity. Females and patients with incident radiographic OA are more likely to meet clinical thresholds for OA.

Gene Expression in Meniscal Tears at the Time of Arthroscopic Partial Meniscectomy Predicts the Progression of Osteoarthritis Within 6 Years of Surgery.

BACKGROUND: While knees with meniscal tears are associated with a heightened risk of developing osteoarthritis (OA), it is difficult to predict which patients are at the greatest risk for OA. Gene signatures in menisci that are resected during arthroscopic partial meniscectomy (APM) may provide insight into the risk of OA progression. HYPOTHESIS: Meniscal gene signatures at the time of APM will predict radiographic OA progression. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Meniscal fragments were collected from 38 patients without OA during clinically indicated APM of the medial meniscus. The expression of 28 candidate genes with known roles in cartilage homeostasis, OA, extracellular matrix degradation, and obesity was assessed by quantitative real-time polymerase chain reaction. Weightbearing radiographs obtained before surgery and at final follow-up were graded by a musculoskeletal radiologist using the Kellgren-Lawrence classification of OA. The association of meniscal gene expression at baseline with the progression of radiographic OA was determined. RESULTS: Gene expression and baseline and follow-up radiographic data were available from 31 patients (81.6%) at a mean follow-up of 6.2 ± 1.3 years. Patients without OA progression had significantly higher expression of 7 genes: MMP9 (5.1-fold; P = .002), IL8 (2.9-fold; P = .016), CCL3 (3.7-fold; P = .032), CCL3L1 (4.5-fold; P = .008), CXCL6 (6.2-fold; P = .010), LEP (5.2-fold; P = .004), and RETN (46-fold; P = .008). CONCLUSION: Gene expression in the meniscus at the time of APM may be associated with the risk for progression of OA after surgery. Elevated expression of the aforementioned genes may reflect a chondroprotective response. Stratifying the risk for OA progression after APM could facilitate targeted interventions to delay or prevent the development of OA. Further studies in a larger cohort with an extended follow-up, and inclusion of additional genes, are warranted to better characterize this association.

Unmasking Intra-tumoral Heterogeneity and Clonal Evolution in NF1-MPNST.

Sarcomas are highly aggressive cancers that have a high propensity for metastasis, fail to respond to conventional therapies, and carry a poor 5-year survival rate. This is particularly true for patients with neurofibromatosis type 1 (NF1), in which 8%-13% of affected individuals will develop a malignant peripheral nerve sheath tumor (MPNST). Despite continued research, no effective therapies have emerged from recent clinical trials based on preclinical work. One explanation for these failures could be the lack of attention to intra-tumoral heterogeneity. Prior studies have relied on a single sample from these tumors, which may not be representative of all subclones present within the tumor. In the current study, samples were taken from three distinct areas within a single tumor from a patient with an NF1-MPNST. Whole exome sequencing, RNA sequencing, and copy number analysis were performed on each sample. A blood sample was obtained as a germline DNA control. Distinct mutational signatures were identified in different areas of the tumor as well as significant differences in gene expression among the spatially distinct areas, leading to an understanding of the clonal evolution within this patient. These data suggest that multi-regional sampling may be important for driver gene identification and biomarker development in the future.

A comparison of 3 routes of flumazenil administration to reverse benzodiazepine-induced desaturation in an animal model.

PURPOSE: The purpose of this study was to examine intralingual (IL) and submucosal (SM) delivery offlumazenil as viable alternatives to immediate intravenous (IV) administration for reversing benzodiazepine sedation in an animal model. METHODS: A dog animal model was chosen based upon comparable body weight to children (12-17 kg) and the ease of oral access in this species. Research design was a nonrandomized matched pair study. This type of "before-and-after study" allowed the dogs to receive 3 different routes of flumazenil administration (IV, IL, and SM) following an initial dose of midazolam (0.5 mg/kg IV). Blood samples were obtained (at 0, 2, 4, 8, 15, and 30 minutes) for high performance liquid chromatography (HPLC) analysis of flumazenil and midazolam, and oxygen saturation values were recorded. RESULTS: Both IL and SM delivery of flumazenil were determined to be viable alternatives to immediate IV administration for reversing benzodiazepine-induced oxygen saturation (SaO2) desaturation. For flumazenil to be able to reverse the SaO2 desaturation, the plasma levels must be greater than 5 ng/ml, which was exceeded by IL and SM drug delivery. CONCLUSION: In a benzodiazepine-induced desaturation, the submucosal and intralingual routes are viable alternatives to intravenous administration of flumazenil in an animal model.