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BackgroundNon-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.MethodsThree cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression.ResultsHigh PD-L1 expression (PD-L1 ≥50%) rate was 19%–20% in classic EGFR, EGFR exon 20 and HER2-mutant tumors, and 34%–55% in tumors with ALK, BRAF V600E, ROS1, RET, or MET alterations. Compared with KRAS-mutant tumors, BRAF non-V600E group had higher TMB (9.6 vs KRAS 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (p<0.001). In the two clinical cohorts treated with ICB, molecular groups with EGFR, HER2, ALK, ROS1, RET, or MET alterations had short progression-free survival (PFS; 1.8–3.7 months), while BRAF V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs KRAS 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs KRAS 24%; PFS 7.4 vs KRAS 2.8 months, HR 0.36, p=0.026). KRAS G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, BRAF V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, p<0.001) were associated with longer PFS.ConclusionsHigh TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK, ROS1, RET, and MET fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations.

Background In the evaluation of PD-L1 expression to select patients for anti-PD-1/PD-L1 treatment, uniform guidelines that account for different immunohistochemistry assays, different cell types and different cutoff values across tumor types are lacking. Data on how different scoring methods compare in breast cancer are scant. Methods Using FDA-approved 22C3 diagnostic immunohistochemistry assay, we retrospectively evaluated PD-L1 expression in 496 primary invasive breast tumors that were not exposed to anti-PD-1/PD-L1 treatment and compared three scoring methods (TC: invasive tumor cells; IC: tumor-infiltrating immune cells; TCIC: a combination of tumor cells and immune cells) in expression frequency and association with clinicopathologic factors. Results In the entire cohort, positive PD-L1 expression was observed in 20% of patients by TCIC, 16% by IC, and 10% by TC, with a concordance of 87% between the three methods. In the triple-negative breast cancer patients, positive PD-L1 expression was observed in 35% by TCIC, 31% by IC, and 16% by TC, with a concordance of 76%. Associations between PD-L1 and clinicopathologic factors were investigated according to receptor groups and whether the patients had received neoadjuvant chemotherapy. The three scoring methods showed differences in their associations with clinicopathologic factors in all subgroups studied. Positive PD-L1 expression by IC was significantly associated with worse overall survival in patients with neoadjuvant chemotherapy and showed a trend for worse overall survival and distant metastasis-free survival in triple-negative patients with neoadjuvant chemotherapy. Positive PD-L1 expression by TCIC and TC also showed trends for worse survival in different subgroups. Conclusions Our findings indicate that the three scoring methods with a 1% cutoff are different in their sensitivity for PD-L1 expression and their associations with clinicopathologic factors. Scoring by TCIC is the most sensitive way to identify PD-L1-positive breast cancer by immunohistochemistry. As a prognostic marker, our study suggests that PD-L1 is associated with worse clinical outcome, most often shown by the IC score; however, the other scores may also have clinical implications in some subgroups. Large clinical trials are needed to test the similarities and differences of these scoring methods for their predictive values in anti-PD-1/PD-L1 therapy.

Factors correlated with biopsy tissue adequacy and the prevalence of within-biopsy variability were evaluated. Totally, 1149 research biopsies were performed on 686 patients from which 5090 cores were assessed. Biopsy cores were reviewed for malignant percentage (estimated percentage of cells in the core that were malignant) and malignant area (estimated area occupied by malignant cells). Linear mixed models and generalized linear mixed models were used for the analysis. A total of 641 (55.8%) biopsies contained a core with <10% malignant percentage (inadequate core). The chance of an inadequate core was not influenced by core order, though the malignant area decreased with each consecutive core ( p  < 0.001). Younger age, bone biopsy location, appendiceal tumor pathology, and responding/stable disease prior to biopsy increased the odds of a biopsy containing zero adequate cores. Within-biopsy variability in core adequacy is prevalent and suggests the need for histological tumor quality assessment of each core in order to optimize translational analyses.

Purpose Chemotherapy side effects diminish quality of life and can lead to treatment delay. Nausea and vomiting can occur prior to chemotherapy because of classical conditioning. We studied the effects of 20‐minute behavioral interventions, administered by oncology nurses, of higher intensity (mindfulness relaxation—MR) or lower intensity (relaxing music—RM), on anticipatory nausea and vomiting (ANV). Patients and methods Patients undergoing chemotherapy for solid tumors were randomized to MR (N = 160), RM (N = 159), or standard care SC (N = 155). Subjects were mostly female (91.8%) and white (86.1%) with breast cancer (85%). Most patients had early stage disease (Stage I: 26%; II: 52.9%; III: 19%; IV: 0.1%). Anticipatory nausea and vomiting were assessed at the midpoint and end of the chemotherapy course using the Morrow Assessment of Nausea and Emesis (MANE). Results Compared to SC, there was reduced anticipatory nausea at the midpoint of chemotherapy in those receiving MR (OR 0.44, 95% CI 0.20‐0.93) and RM (OR 0.40, 95% CI 0.20‐0.93), controlling for age, sex, cancer stage, and emetogenic level of chemotherapy. There was no difference between treatment groups in anticipatory nausea at the end of chemotherapy or in anticipatory vomiting and postchemotherapy nausea and vomiting at either time point. Conclusion A brief nurse‐delivered behavioral intervention can reduce midpoint ANV associated with chemotherapy. Chemotherapy administration can result in conditioned nausea and vomiting. This multi‐centred randomized controlled trial demonstrates the superiority of 2 preemptive behavioural interventions in reducing conditioned nausea.

Background MUC18 is a glycoprotein highly expressed on the surface of melanoma and other cancers which promotes tumor progression and metastasis. However, its mechanism of action and suitability as a therapeutic target are unknown. Methods A monoclonal antibody (mAb) (JM1-24-3) was generated from metastatic melanoma tumor live cell immunization, and high-throughput screening identified MUC18 as the target. Results Analysis of molecular interactions between MUC18 and JM1-24-3 revealed that the downstream signaling events depended on binding of the mAb to a conformational epitope on the extracellular domain of MUC18. JM1-24-3 inhibited melanoma cell proliferation, migration and invasion in vitro and reduced tumor growth and metastasis in vivo. Conclusion These results confirm that MUC18 is mechanistically important in melanoma growth and metastasis, suggest that the MUC18 epitope identified is a promising therapeutic target, and that the JM1-24-3 mAb may serve as the basis for a potential therapeutic agent.

Basal cell carcinomas are the most common form of skin cancer. Tazarotene is a retinoic acid receptor selective retinoid that upregulates a tumor suppressor, tazarotene-induced gene 3 (TIG-3), in keratinocytes and psoriasis. Expression of TIG-3 in basal cell carcinomas was studied in an opened-label pilot biomarker study of 22 patients with basal cell carcinomas who applied tazarotene 0.1% gel for up to 12 wk prior to excision. Nineteen paired baseline and treated specimens were compared using immunohistochemistry and in situ hybridization. Compared to overlying normal epidermis, TIG-3 protein and mRNA were decreased in 14 and 18 of 19 basal cell carcinomas (74% and 95%), respectively (p<0.001). Tazarotene treatment was associated with increased TIG-3 protein and mRNA expression in basal cell carcinomas compared to baseline levels (p≤0.001 and p=0.028, respectively). Sixty percent of basal cell carcinomas treated with tazarotene decreased in size by at least 25%. Ten of 19 lesions improved histologically, including three complete responses. There was a correlation between the increased expression of TIG-3 protein and histologic improvement (p=0.020), suggesting that suppression of TIG-3 may underlie the development of basal cell carcinomas. This association suggests that reversal of TIG-3 expression may help to explain the mechanism of retinoid action in epidermal differentiation and chemoprevention.

Background The benefit of adrenalectomy (ADX) for adrenal metastasis is not established. We evaluated outcomes after ADX for patients with adrenal metastasis. Methods We retrospectively analyzed the records of 90 patients who underwent ADX for metastatic disease. Overall survival (OS) after ADX was calculated using the Kaplan–Meier method. Clinical factors were evaluated for associations with OS using a Cox regression model, and with operative factors using the Wilcoxon two-sample or Fisher’s exact test. Results The most common primary tumor types were melanoma (35, 39 %) and lung cancer (32, 35 %). A total of 49 (54 %) patients had isolated adrenal metastasis; 55 (61 %) underwent laparoscopic resection (LADX). Median OS was 2.46 years (range < 1 month–15 years), and 5-year survival rate was 38 % (6 % standard error). Most patients experienced disease progression (56, 62 %) despite achieving disease-free status following ADX (78, 86 %). When compared with the open approach, LADX was associated with smaller tumor size, as well as reduced blood loss, operative time, and length of stay (all p  < 0.0001), and no difference in OS ( p  = 0.4122) or complications ( p  = 1). Isolated adrenal bed recurrence was similar in LADX ( N  = 3, 5 %) and open ADX ( N  = 2, 6 %) ( p  = 1), and did not affect OS ( p  = 0.2). Larger tumors were associated with shorter median OS ( p  = 0.0014). Conclusions ADX for metastasis can be safely performed in selected patients. Some patients with adrenal metastasis achieve prolonged survival following ADX. Compared with an open approach, LADX has no measurable oncologic disadvantage, minimizes morbidity, and should be considered when tumor characteristics permit.

This study examined coping styles and attributions for negative events among chronically depressed outpatients to determine whether these variables mediated differences in depression treatment outcome between combined nefazodone and cognitive behavioral analysis system of psychotherapy (CBASP), versus nefazodone and CBASP alone. Chronically depressed outpatients ( N  = 517) who completed the initial 12-week treatment phase were included in the analyses. Attributional style and coping met criteria for partial mediation of the combination treatment effect over nefazodone, accounting for 60% of the difference in treatment outcome. Escape-avoidant coping met criteria for partial mediation of the combination treatment effect over CBASP, accounting for 37% of the treatment differential. Among all of the cognitive and coping variables evaluated, escape-avoidance coping emerged as the dominant mediating variable. These findings suggest that nefazodone and CBASP each produced changes in maladaptive cognitions and coping, and that the superiority of combined treatment was partially accounted for by the additive effects of both forms of treatment on these variables.

Recent investigation has identified association of IL-12p40 blood levels with melanoma recurrence and patient survival. No studies have investigated associations of single-nucleotide polymorphisms (SNPs) with melanoma patient IL-12p40 blood levels or their potential contributions to melanoma susceptibility or patient outcome. In the current study, 818,237 SNPs were available for 1,804 melanoma cases and 1,026 controls. IL-12p40 blood levels were assessed among 573 cases (discovery), 249 cases (case validation), and 299 controls (control validation). SNPs were evaluated for association with log[IL-12p40] levels in the discovery data set and replicated in two validation data sets, and significant SNPs were assessed for association with melanoma susceptibility and patient outcomes. The most significant SNP associated with log[IL-12p40] was in the IL-12B gene region (rs6897260, combined P=9.26 × 10−38); this single variant explained 13.1% of variability in log[IL-12p40]. The most significant SNP in EBF1 was rs6895454 (combined P=2.24 × 10−9). A marker in IL12B was associated with melanoma susceptibility (rs3213119, multivariate P=0.0499; OR=1.50, 95% CI 1.00–2.24), whereas a marker in EBF1 was associated with melanoma-specific survival in advanced-stage patients (rs10515789, multivariate P=0.02; HR=1.93, 95% CI 1.11–3.35). Both EBF1 and IL12B strongly regulate IL-12p40 blood levels, and IL-12p40 polymorphisms may contribute to melanoma susceptibility and influence patient outcome.

Background Subdiaphragmatic paraganglioma is a rare neuroendocrine tumor for which scarce data exist regarding long-term patient outcome following resection. The aim of this study was to determine the association of surgical resection with survival. Methods A retrospective study at a tertiary care center was performed. Demographics, genetics, histology, and operative details were reviewed. Patients were grouped according to margin status (R0, R1, or R2) and survival calculated. Results A total of 50 patients with subdiaphragmatic paragangliomas underwent primary resection from 1999 to 2012. Median age at operation was 46 years, with a median tumor size of 6.0 cm. Of these patients, 30 (60 %) had a R0 resection, 11 (22 %) had a R1 resection, and 9 (18 %) had a R2 resection. There was no operative mortality, and 17 (34 %) patients had metastatic disease. Six (12 %) patients died, four (8 %) of whom had metastatic disease. Univariate analysis identified that age >50 years ( p = 0.02) and undergoing a R2 resection ( p = 0.03) were associated with a shorter overall survival (OS). Those with metastases at some point after their initial diagnosis had a shorter disease-free survival (DFS) than those without metastases ( p = 0.04). Of 27 patients tested, 12 (44 %) had a germline succinyl dehydrogenase B (SDHB) mutation. SDHB immunohistochemistry identified 18 patients (of 27 who underwent staining) who had loss of SDHB expression in which 7 of 11 patients (63 %) who underwent genetic testing had a genetic mutation. Conclusions Surgical resection of subdiaphragmatic paraganglioma is safe. Survival was longest in patients who were younger, with no metastases, or had a R0 or R1 resection. Patients who test negative for a germline mutation should undergo SDHB immunostaining to identify potential hereditary carriers missed by current genetic testing.