The Impact of Local Control on Overall Survival after Y-90 Selective Internal Radiotherapy of Liver Metastases in Oligometastatic Cancer: A Retrospective Analysis.

Y-90 Selective Internal Radiotherapy (SIRT) is an ablative therapy used for inoperable liver metastasis. The purpose of this investigation was to examine the impact of local control after SIRT on overall survival (OS) in oligometastatic patients. A retrospective, single-institution study identified oligometastatic patients with ≤5 non-intracranial metastases receiving unilateral or bilateral lobar Y-90 SIRT from 2009 to 2021. The primary endpoint was OS defined from Y-90 SIRT completion to the date of death or last follow-up. Local failure was classified as a progressive disease at the target lesion(s) by RECIST v1.1 criteria starting at 3 months after SIRT. With a median follow-up of 15.7 months, 33 patients were identified who had a total of 79 oligometastatic lesions treated with SIRT, with the majority histology of colorectal adenocarcinoma (n = 22). In total, 94% of patients completed the Y-90 lobectomy. Of the 79 individual lesions treated, 22 (27.8%) failed. Thirteen patients received salvage liver-directed therapy following intrahepatic failure; ten received repeat SIRT. Median OS (mOS) was 20.1 months, and 12-month OS was 68.2%. Intralesional failure was associated with worse 1 y OS (52.3% vs. 86.2%, p = 0.004). These results suggest that intralesional failure following Y-90 may be associated with inferior OS, emphasizing the importance of disease control in low-metastatic-burden patients.

Oncogenic fusions: Targeting NTRK.

Non-Small Cell Lung Cancer (NSCLC) is responsible for the highest number of cancer-related deaths in the United States. Thankfully, advancements in the detection and targeting of gene mutations have greatly improved outcomes for many patients. One significant mutation driving oncogenesis in various cancers, including NSCLC, is the neurotrophic tyrosine receptor kinase (NTRK) fusion. Presently, larotrectinib and entrectinib are the only FDA-approved therapies for NTRK-mutated cancers. Despite the efficacy and tolerability exhibited by these therapies, several clinical hurdles persist for physicians, including resistance mutations and limited penetration of the central nervous system (CNS), which diminishes their effectiveness. The treatment landscape for NTRK cancers is still being explored, with numerous new tyrosine kinase inhibitors currently in development or undergoing phase 1 and 2 clinical trials. In this review, we delve into both established and novel therapies targeting NTRK-mutated NSCLC.

Comprehensive Review of ROS1 Tyrosine Kinase Inhibitors-Classified by Structural Designs and Mutation Spectrum (Solvent Front Mutation [G2032R] and Central ß-Sheet 6 [Cß6] Mutation [L2086F]).

Despite ROS1 fusion-positive NSCLC accounting for approximately 1% to 2% of NSCLC, there is a long list of ROS1 tyrosine kinase inhibitors (TKIs) being developed in addition to three approved ROS1 TKIs, crizotinib, entrectinib and repotrectinib. Here, we categorized ROS1 TKIs by their structures (cyclic versus noncyclic) and inhibitory abilities (active against solvent front mutation G2032R or central ß-sheet #6 [Cß6] mutation L2086F) and summarized their reported clinical activity in order to provide a dashboard on how to use these ROS1 TKIs in various clinical situations. In addition, the less known Cß6 mutation ROS1 L2086F confer resistances to next-generation ROS1 TKIs (repotrectinib, taletrectinib, and potentially NVL-520) that can be overcome by cabozantinib as documented in published patient reports and potentially by certain L-shaped type I ROS1 TKIs including ceritinib and gilteritinib, which is approved as a FLT3 inhibitor for relapsed refractory FLT3+ acute myeloid leukemia but have published preclinical activites against ROS1 (and ALK). Future clinical trials should investigate cabozantinib and gilteritinib to repurpose them as ROS1 TKIs that can target ROS1 L2086F Cß6 mutation.

Osimertinib tolerance in a patient with Stevens Johnson syndrome during osimertinib therapy after treatment with pembrolizumab.

BACKGROUND: Osimertinib has emerged as an important tool in the treatment of non-small cell lung cancers (NSCLC) with certain activating mutations of epidermal growth factor receptor (EGFR). However, Osimertinib may cause adverse effects, including severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The risk of certain adverse effects may be increased in the setting of recent use of immune checkpoint inhibitor (ICI) therapy, although it is unclear whether recent use of ICI therapy is a risk factor for Osimertinib-induced SJS specifically. CASE PRESENTATION: We present a patient with EGFR L858R mutation-positive metastatic NSCLC who developed Osimertinib-induced SJS after recent administration of eight cycles of a pembrolizumab-containing chemotherapy regimen. Osimertinib, which was the best treatment targeting his lung cancer, was avoided due to history of SJS. Four years later, because of unresponsiveness or side effects of alternative treatments, he underwent Osimertinib challenge and tolerated it. CONCLUSION: This case highlights the importance of multi-disciplinary care and supports the hypothesis that the risk of SJS to Osimertinib is significantly higher in the context of recent administration of ICI therapy and, patients may tolerate Osimertinib after certain time has elapsed after the last dose of ICI.

Neoadjuvant therapy in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) stages I-III were previously predominantly treated with surgery and chemotherapy. With the advent of Checkmate-816, neoadjuvant nivolumab and chemotherapy was FDA approved for the treatment of resectable NSCLC. There are several ongoing trials evaluating other neoadjuvant combinations of chemotherapy and immunotherapy as well as targeted therapies towards driver mutations. Here, we review previous clinical trials and discuss current ongoing trials' potential benefits and challenges.

Proteolysis targeting chimeras in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) has very poor prognosis in advanced stages. Discovery and application of therapies targeting specific oncogenic driver mutations has greatly improved overall survival. However, targeted therapies are limited in their efficacy due to resistance mutations that may arise with long term use. Proteolysis targeting Chimeras (PROTACs) are a promising approach to combating resistance mutations. PROTACs commandeer innate ubiquitination machinery to degrade oncogenic proteins. Here we review the PROTACs that have been developed for targeting common EGFR, KRAS, and ALK mutations.

Cryoglobulinemia Leading to the Diagnosis of Low Grade Serous Ovarian Carcinoma.

We present the case of a 64-year-old female who was referred by her oncologist to benign hematology clinic for persistent asymptomatic cryoglobulinemia. Workup led to diagnosis of a rare low grade ovarian serous carcinoma. We briefly review the pathophysiology and clinical significance of cryoglobulinemia and the diagnosis and management of low grade serous ovarian carcinoma.

A Journey From Appendicitis to a Rare Appendiceal Mucinous Neoplasm.

We present here a 66-year-old Caucasian male whose persistent abdominal pain thought to be due to appendicitis and associated acute splanchnic thrombosis. He was initially managed with antibiotics and anticoagulation. But further work up revealed a low-grade appendiceal mucinous neoplasm causing the splanchnic vein thrombosis. Additionally, diagnosis and management of this rare tumor and appropriate work up for splanchnic thrombosis will be briefly reviewed here.

Durable Responses in Patients With Advanced Cholangiocarcinoma on Sequential Dual-agent Immunotherapy After Progressing on Single-agent Immunotherapy.

OBJECTIVES: Biliary tract tumors have a poor prognosis despite advancements in targeted therapies. More recent studies have started to investigate the use of combination immunotherapy in advanced biliary cancers. However, currently, there are no clinical trials investigating the use of dual-agent immunotherapy with ipilimumab and nivolumab as a sequential treatment after patients have progressed on single-agent immunotherapy. In this case series, we discussed 3 patients with advanced cholangiocarcinoma who have an objective response to dual-agent immunotherapy with ipilimumab and nivolumab after having disease progression on pembrolizumab and multiple other failed lines of treatment. MATERIALS AND METHODS: A case series, including 3 patients treated at the University of California, Irvine Chao Family Comprehensive Cancer Center, was completed. RESULTS: Although none of the 3 patients had microsatellite instability or high tumor-mutation burden and were not necessarily predicted to have a response to dual-agent immunotherapy, all 3 patients had an objective radiographic and/or tumor-marker response to a combination of ipilimumab and nivolumab. CONCLUSIONS: This case series serves as proof of the concept that sequential immunotherapy can be beneficial after progression on single-agent immunotherapy for patients with advanced cholangiocarcinoma. This study can also serve as the foundation to build further tests on the true effectiveness and ideal duration of sequential therapy with dual immunotherapy agents.

Tonic Calcium-Activated Chloride Current Sustained by ATP Release and Highly Desensitizing Human P2X1 Receptors.

Extracellular adenosine triphosphate (ATP) participates in maintaining the vascular tone in the CNS, particularly in the retina, via the tonic activity of ligand gated activated P2X1 receptors. P2X1 receptors are characterized by their high affinity for ATP and their strong desensitization to concentrations of ATP that are 200-fold lower than their EC50. The mechanism behind P2X1 tonic activity remains unclear. In this study, we expressed human P2X1 (hP2X1) homomeric receptors in Xenopus oocytes to explore the relationship between ATP release from oocytes at rest, hP2X1, and Ca2+-activated Cl- channels. Our results indicate that Xenopus oocytes release ATP at rest via vesicular exocytosis, and this process is a constitutive phenomenon independent of extracellular Ca2+. Our results also indicate that hP2X1 receptors are able to sustain a tonic activity of Ca2+-activated Cl- channels. In the presence of extracellular Ca2+ the activity of hP2X1 receptors is greatly amplified by its coupling with Ca2+-activated Cl- channels. Future studies addressing the relationship between hP2X1 receptors and Ca2+-activated Cl- channels in vascular smooth muscle cells should provide information about additional mechanisms that regulate the vascular tone and their potential as pharmaceutical targets. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.