Physical and Psychological Impact of the Covid-19 Pandemic on Healthcare Workers, Including End of Life Care Providers.

Background: The COVID-19 pandemic has not only caused unprecedented distress in the community but has also resulted in significant physical and psychological exhaustion among healthcare workers (HCWs). This exhaustion could potentially lead to serious effects on our healthcare system. Objective: The aim of this study was to gain more insight on the effect of COVID-19 on burnout among oncologists and other healthcare professionals at a large academic center. Methods: A 10-minute electronic questionnaire was distributed to actively employed physicians, APRNs, and PAs affiliated with the University of Miami. The survey encompassed a range of personal and professional characteristics, including stress related to COVID-19. Results: The survey was distributed to a total of 739 HCWs, with 182 respondents (24.6%) completing the entire survey. The impact of the pandemic on these professionals included increased workload (59.5%), reduced leadership opportunities (32.2%), job insecurity (28.6%), and rescheduling of professional activities (22.2%). Out of the 182 respondents, 70 were primarily from the fields of Oncology and Palliative Care. Conclusions: Several factors have contributed to increased physical and psychological stress among HCWs, such as extended working hours, sleep deprivation, job insecurity, the shift to telemedicine, the risk of contracting the virus and endangering their families, lack of childcare options, and the added pressure of homeschooling. This study serves as a foundation for more comprehensive research aimed at elucidating and guiding the development of wellness programs crucial for the overall well-being of HCWs.

Therapeutic strategies for BRAF mutation in non-small cell lung cancer: a review.

Lung cancer is the leading cause of cancer related deaths. Among the two broad types of lung cancer, non-small cell lung cancer accounts for 85% of the cases. The study of the genetic alteration has facilitated the development of targeted therapeutic interventions. Some of the molecular alterations which are important targets for drug therapy include Kirsten rat sarcoma (KRAS), Epidermal Growth Factor Receptor (EGFR), V-RAF murine sarcoma viral oncogene homolog B (BRAF), anaplastic lymphoma kinase gene (ALK). In the setting of extensive on-going clinical trials, it is imperative to periodically review the advancements and the newer drug therapies being available. Among all mutations, BRAF mutation is common with incidence being 8% overall and 1.5 - 4% in NSCLC. Here, we have summarized the BRAF mutation types and reviewed the various drug therapy available - for both V600 and nonV600 group; the mechanism of resistance to BRAF inhibitors and strategies to overcome it; the significance of comprehensive profiling of concurrent mutations, and the role of immune checkpoint inhibitor in BRAF mutated NSCLC. We have also included the currently ongoing clinical trials and recent advancements including combination therapy that would play a role in improving the overall survival and outcome of NSCLC.

Efficacy and outcomes of ramucirumab and docetaxel in patients with metastatic non-small cell lung cancer after disease progression on immune checkpoint inhibitor therapy: Results of a monocentric, retrospective analysis.

Current first-line standard therapy for metastatic non-small cell lung cancer without driver mutations involves chemotherapy and immunotherapy combination. Prior to the advent of immune checkpoint inhibition, REVEL, a randomized phase III trial demonstrated improved progression-free and overall survival with ramucirumab and docetaxel (ram+doc) in patients who failed platinum-based first-line therapy. Long-term outcomes related to second-line ramucirumab and docetaxel after first-line immunotherapy exposure remain unknown. We analyzed outcomes for 35 patients from our center whom received ramucirumab and docetaxel following disease progression on chemotherapy and immunotherapy combination. Median progression-free survival among patients who received ram+doc after exposure to immunotherapy was 6.6 months (95% CI = 5.5 to 14.9 months; p<0.0001), and median overall survival was 20.9 months (95% CI = 13.4 months to infinity; p<0.0001). These outcomes suggest that there may a synergistic benefit to combining chemotherapy with anti-angiogenic therapy after immunotherapy exposure. Future analyses should be evaluated prospectively and among a larger patient subset.

Therapeutic strategies in RET gene rearranged non-small cell lung cancer.

The recent approvals by the Food and Drug Administration several tumor-agnostic drugs have resulted in a paradigm shift in cancer treatment from an organ/histology-specific strategy to biomarker-guided approaches. RET gene fusions are oncogenic drivers in multiple tumor types and are known to occur in 1-2% of non-squamous NSCLC patients. RET gene fusions give rise to chimeric, cytosolic proteins with constitutively active RET kinase domain. Standard therapeutic regimens provide limited benefit for NSCLC patients with RET fusion-positive tumors, and the outcomes with immunotherapy in the these patients are generally poor. Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are potent and selective inhibitors that target RET alterations, including fusions and mutations, irrespective of the tissue of origin. Recently, the results from the LIBRETTO-001 and ARROW clinical trials demonstrated significant clinical benefits with selpercatinib and pralsetinib respectively, in NSCLC patients with RET gene fusions, with tolerable toxicity profiles. These studies also demonstrated that these RET-TKIs crossed the blood brain barrier with significant activity. As has been observed with other TKIs, the emergence of acquired resistance may limit long-term efficacy of these agents. Therefore, understanding the mechanisms of resistance is necessary for the development of strategies to overcome them.

Therapeutic strategies in METex14 skipping mutated non-small cell lung cancer.

METex14 skipping mutations occur in about 3-4% of lung adenocarcinoma patients and 1-2% of patients with other lung cancer histology. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are established oncogenic drivers of NSCLC. A mutation that results in loss of exon 14 in the MET gene leads to dysregulation and inappropriate signaling that is associated with increased responsiveness to MET TKIs. Results from GEOMETRY mono-1 and VISION Phase I/II clinical trials demonstrated significant clinical activity in patients treated with the MET Exon 14 skipping mutation inhibitors capmatinib and tepotinib with tolerable toxicity profile. In the GEOMETRY mono-1 trial, capmatinib was especially active in treatment-naïve patients supporting the upfront testing of this oncogenic driver. Tepotinib demonstrated superior activity in the pretreated patients in the VISION trial. Savolitinib is another MET TKI that has shown efficacy in the first- and second-line settings, including patients with aggressive pulmonary sarcomatoid carcinoma. These studies have demonstrated that these TKIs can cross the blood brain barrier and demonstrated some activity toward CNS metastases. MET Exon 14 skipping mutation is detected by NGS-based testing of liquid or tissue biopsies, with preference for RNA-based NGS. The activity of capmatinib and tepotinib is limited by the development of acquired resistance. Current research is focused on strategies to overcome resistance and improve the effectiveness of these agents. Our aim is to review the current status of MET Exon 14 skipping mutation as it pertains NSCLC.

Secondary gliosarcoma with extra-cranial metastases: a report and review of the literature.

OBJECTIVE: To describe a unique case of secondary gliosarcoma (SGS) with widespread extra-cranial metastases that developed more than 5 years after the initial diagnosis of glioblastoma multiforme (GBM). This interval is the longest among the cases reported to date. METHODS: A PUBMED search using the key words "secondary gliosarcoma" and "extra-cranial metastases" was performed followed by a review of cited literature. RESULTS: Including our report, we found 44 cases of SGS, of which only 5 developed extra-cranial metastases. CONCLUSION: SGS with extra-cranial metastases is extremely rare. Of previously reported cases, the longest survival was 2 months after the diagnosis of SGS. The present case had a survival of 6.5 months. Our case highlights the importance of screening for extra-cranial metastases in SGS. The optimal treatment of SGS is not known and strategies based on GBM and sarcoma treatments have been employed with limited success. A combination of treatment modalities may extend survival as in the present report; however the prognosis remains poor.

The emerging role of lenalidomide in the management of mantle cell lymphoma (MCL).

Mantle cell lymphoma (MCL) is considered an aggressive and incurable B-cell malignancy despite current available treatments that include the incorporation of rituximab, bortezomib, high-dose cytarabine, and for those eligible, high dose chemotherapy and autologous bone marrow transplant (HDC-ASCT). Patients with relapsed/refractory MCL represent a challenge for the treating physician stressing the need to develop therapeutic agents. Lenalidomide, a novel inmmunomodulatory drug (IMiD), is a promising therapeutic strategy for patients with relapsed/refractory B-cell lymphoma. Biologically, the mechanisms responsible for lenalidomide activity are yet to be clearly defined. Based on pre-clinical models and early correlative studies conducted parallel to clinical trials, lenalidomide has been found to enhance NK-cell and T-cell activity against tumor cells, alter the balance of pro- and anti-inflammatory cytokines in the tumor bed, inhibit angiogenesis, and to a lesser degree, induce cell cycle arrest and apoptosis in cancer cells. Together, all these biological effects appear to play a role in the activity observed in lymphoma patients treated with lenalidomide. Given the effect in NK- and T-cell function, lenalidomide is an alternative strategy to enhance the anti-tumor activity of monoclonal antibodies (mAbs). Clinical responses have been observed in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), follicular lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma (DLBCL), and MCL. The favorable toxicity profile and route of administration made the use of lenalidomide an attractive therapy for certain types of patients (i.e. elderly, chemotherapy unfit, etc.). The erratic but serious incidence of tumor lysis syndrome and/or tumor flare reactions provides challenges in the incorporation of lenalidomide in the management of previously untreated lymphoma patients with bulky adenopathy. Early studies evaluating the efficacy and toxicity of lenalidomide in combination with steroids or rituximab/bendamustine in MCL are promising and warrant further study. In addition, the evaluation of lenalidomide in the maintenance setting (i.e. post HDC-ASCT) or in combination with other target specific agents (i.e. proteasome inhibitors) in MCL is being addressed in ongoing clinical trials. We provide a general overview of the clinical development of lenalidomide in MCL. Future translational and clinical studies will further define the role of lenalidomide in the management of de novo or relapsed/refractory MCL and may assist in the identification of subset of MCL patients most likely to gain clinical benefit from this exiting agent.