Research Spotlight

Planchard, D., B. Besse, H. J. M. Groen, S. M. S. Hashemi, J. Mazieres, T. M. Kim, E. Quoix, P. J. Souquet, F. Barlesi, C. Baik, L. C. Villaruz, R. J. Kelly, S. Zhang, M. Tan, E. Gasal, L. Santarpia and B. E. Johnson (2021). “Phase 2 study of dabrafenib plus trametinib in patients with BRAF V600E-mutant metastatic non-small cell lung cancer: Updated 5-year survival rates and genomic analysis.” J Thorac Oncol Aug 26;S1556-0864(21)02403-5. [Epub ahead of print].

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INTRODUCTION: Dabrafenib plus trametinib demonstrated robust antitumour activity in patients with BRAF V600E-mutant metastatic non-small cell lung cancer (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data. METHODS: Pretreated (cohort B) and treatment-naïve (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumours version 1.1. Secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: At data cut-off, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range, 0.5-78.5) and 16.3 (range, 0.4-80) months, ORR (95% CI) was 68.4% (54.8-80.1) and 63.9% (46.2-79.2), median PFS (95% CI) was 10.2 (6.9-16.7) and 10.8 (7.0-14.5) months, and median OS (95% CI) was 18.2 (14.3-28.6) and 17.3 (12.3-40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naïve patients, respectively. Seventeen (18%) patients were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation. CONCLUSIONS: Dabrafenib plus trametinib therapy demonstrated substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of prior treatment.

Budhiraja, P., M. A. Kalot, A. E. Alayli, A. Dimassi, B. Kaplan, H. A. Chakkera and R. A. Mustafa (2021). “Reporting and Handling of Missing Participant Data in Systematic Reviews of Kidney Transplant Studies.” Transplantation 105(8): 1708-1717.

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BACKGROUND: Participant withdrawal from clinical trials occurs for various reasons, predominantly adverse effects or intervention inefficacy. Because these missing participant data can have implications for the validity, reproducibility, and generalizability of study results, when conducting a systematic review, it is important to collect and appropriately analyze missing data information to assess its effects on the robustness of the study results. METHODS: In this methodologic survey of missing participant data reporting and handling in systematic reviews, we included meta-analyses that provided pooled estimates of at least 1 dichotomous intervention outcome of a randomized controlled trial performed in adult kidney transplant subjects. RESULTS: Eighty-three systematic reviews (17 Cochrane and 66 non-Cochrane reviews) met the inclusion criteria. The most common intervention was drugs (80%), with the majority involving immunosuppressant drugs 55% (n = 46), followed by surgery in 14% (n = 12). The median follow-up duration was 12 months (maximum, 240 mo). Intention-to-treat or modified intention-to-treat analysis was reported in 24% (n = 20) of the reviews (76% of Cochrane and 10% of non-Cochrane). Overall, the majority of systematic reviews did not quantify (90% [n = 60] non-Cochrane and 29% [n = 5] Cochrane) or include the reasons for missing participant data (88% [n = 58] non-Cochrane and 24% [n = 4] Cochrane). Eleven percent (n = 9) handled missing participant data, 5% (n = 4) justified the analytical method(s) used to handle it, and 2% (n = 2) performed a sensitivity analysis for it. CONCLUSIONS: Systematic reviews of kidney transplantation provide inadequate information on missing participant data and usually do not handle or discuss the associated risk of bias with it.

Kandimalla, R., W. Wang, F. Yu, N. Zhou, F. Gao, M. Spillman, L. Moukova, O. Slaby, B. Salhia, S. Zhou, X. Wang and A. Goel (2021). “OCaMIR-A Noninvasive, Diagnostic Signature for Early-Stage Ovarian Cancer: A Multi-cohort Retrospective and Prospective Study.” Clin Cancer Res 27(15): 4277-4286.

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PURPOSE: Due to the lack of effective screening approaches and early detection biomarkers, ovarian cancer has the highest mortality rates among gynecologic cancers. Herein, we undertook a systematic biomarker discovery and validation approach to identify microRNA (miRNA) biomarkers for the early detection of ovarian cancer. EXPERIMENTAL DESIGN: During the discovery phase, we performed small RNA sequencing in stage I high-grade serous ovarian cancer (n = 31), which was subsequently validated in multiple, independent data sets (TCGA, n = 543; GSE65819, n = 87). Subsequently, we performed multivariate logistic regression-based training in a serum data set (GSE106817, n = 640), followed by its independent validation in three retrospective data sets (GSE31568, n = 85; GSE113486, n = 140; Czech Republic cohort, n = 192) and one prospective serum cohort (n = 95). In addition, we evaluated the specificity of OCaMIR, by comparing its performance in several other cancers (GSE31568 cohort, n = 369). RESULTS: The OCaMIR demonstrated a robust diagnostic accuracy in the stage I high-grade serous ovarian cancer patients in the discovery cohort (AUC = 0.99), which was consistently reproducible in both stage I (AUC = 0.96) and all stage patients (AUC = 0.89) in the TCGA cohort. Logistic regression-based training and validation of OCaMIR achieved AUC values of 0.89 (GSE106817), 0.85 (GSE31568), 0.86 (GSE113486), and 0.82 (Czech Republic cohort) in the retrospective serum validation cohorts, as well as prospective validation cohort (AUC = 0.92). More importantly, OCaMIR demonstrated a significantly superior diagnostic performance compared with CA125 levels, even in stage I patients, and was more cost-effective, highlighting its potential role for screening and early detection of ovarian cancer. CONCLUSIONS: Small RNA sequencing identified a robust noninvasive miRNA signature for early-stage serous ovarian cancer detection.

Cho, S. M., D. Floden, K. Wallace, N. Hiivala, S. Joseph, J. Teuteberg, J. G. Rogers, F. D. Pagani, N. Mokadam, D. Tirschwell, S. Li, R. C. Starling, C. Mahr and K. Uchino (2021). “Long-Term Neurocognitive Outcome in Patients With Continuous Flow Left Ventricular Assist Device.” JACC Heart Fail Sep 1;S2213-1779(21)00274-2. [Epub ahead of print].

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OBJECTIVES: The authors sought to examine the long-term cognitive outcome of patients with continuous flow left ventricular assist device (CF-LVAD). BACKGROUND: Data on long-term neurocognitive outcome in LVAD are limited. We examined the neurocognitive outcome of patients who received a CF-LVAD as destination therapy. METHODS: Patients with HeartWare (HVAD) and HeartMate II who were enrolled in the ENDURANCE and ENDURANCE Supplemental trials were eligible. Cognition was evaluated with neuropsychological testing preoperatively and at 6, 12, and 24 months after implantation. General linear models identified demographic, disease, and treatment factors that predicted decline on each neurocognitive measure. RESULTS: Of 668 patients who completed baseline testing and at least 1 follow-up evaluation, 552 were impaired at baseline on at least 1 cognitive measure. At each follow-up, approximately 23% of tested patients declined and 20% improved relative to baseline on at least 1 cognitive measure. Of those who were intact at baseline, only 10%-12% declined in delayed memory and 11%-16% declined in executive function at all 3 follow-ups. For patients impaired at baseline, delayed memory decline was associated with the HVAD device and male sex, whereas executive function decline was associated with the HVAD device and stroke during CF-LVAD support. For patients intact at baseline, male sex and history of hypertension were associated with decline in immediate memory and executive function, respectively. CONCLUSION: Neurocognitive function remained stable or improved for most patients (∼80%) with CF-LVAD at 6, 12, and 24 months after implantation. Male sex, hypertension, HVAD, and stroke were associated with cognitive decline.

Karime, C., M. Ijaz, I. R. Kugasia, A. Khan and G. S. Schwartz (2021). “A 49-Year-Old Woman With Persistent Bilateral Pleural Effusions.” Chest 160(3): e273-e278.

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A 49-year-old woman presented to the ED with sudden onset abdominal pain, nausea, and vomiting. Her medical history included an uncomplicated gastric lap band surgery 9 years ago and subsequent removal of lap band after 6 years. She had a Roux-en-Y gastric bypass and cholecystectomy 5 months prior to the current presentation. The patient had been diagnosed with asthma and was prescribed an inhaled corticosteroid that she used only as needed. The patient denied smoking and heavy alcohol consumption. She was currently employed as a scrub technician in a local surgical center.