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.

Meal Eating Characteristics of Patients with Gastroparesis.

BACKGROUND: Patients with gastroparesis often consume only small meals due to early satiety. AIMS: (1) Describe meal eating characteristics of patients with gastroparesis; (2) Relate meal eating characteristics to symptoms, gastric emptying (GE), and body weight. METHODS: Patients with gastroparesis filled out questionnaires including Patient Assessment of Upper GI Symptoms (PAGI-SYM), and questionnaire about meal habits and body weight. Patients underwent gastric emptying scintigraphy. RESULTS: Of 192 gastroparesis patients, 93% endorsed early satiety (ES) with severity of 3.7 ± 1.5 (scored from 0-5) and 93% endorsed postprandial fullness (PPF) with severity of 3.9 ± 1.3. Time spent consuming meals averaged 13.6 ± 17.7 min. Main reasons patients stopped eating were fullness (61%), nausea (48%), and abdominal pain (31%). Time spent eating correlated inversely with severity of nausea (r = -0.18, p < 0.05), stomach fullness (r = -0.21, p < 0.01), PPF (r = -0.23, p < 0.01), loss of appetite (r = -0.34, p < 0.01). Postprandial fullness lasted for 316 ± 344 min. Duration of PPF correlated with nausea (r = 0.30, p < 0.01), retching (r = 0.29, p < 0.01), vomiting (r = 0.28, p < 0.01), stomach fullness (r = 0.33, p < 0.01), loss of appetite (r = 0.35, p < 0.01), and constipation (r = 0.27, p < 0.01). Underweight patients had increased inability to finish a normal size meal (p < 0.01), loss of appetite (p < 0.01), and lower abdominal pain/discomfort (p < 0.05). Patients had lost 3.06 ± 10.60 kgs from their baseline weight. Weight loss correlated with nausea (r = 0.26, p < 0.01), ES (r = 0.30, p < 0.01), loss of appetite (r = 0.28, p < 0.01). CONCLUSIONS: Early satiety and postprandial fullness were common with high severity. The main reasons for meal cessation were early satiety, nausea, and abdominal pain. Body weight and change in body weight were associated with symptoms of gastroparesis.

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.

Functional Reorganization of Local Circuit Connectivity in Superficial Spinal Dorsal Horn with Neuropathic Pain States.

The spinal dorsal horn is the first relay structure coding for pain transmission and modulation. Previous anatomical and electrophysiological studies have examined spinal dorsal horn circuit connections and network activity. Further work is required to understand spinal cord sensory information processing that underlies pathological neuropathic pain states. Our previous studies suggest that peripheral nerve injury enhances presynaptic excitatory input onto spinal superficial dorsal horn neurons, which in turn contributes to pathologic nociception. The potential changes in local postsynaptic circuits in the dorsal horn that lead to pathologically heightened behavioral responses to pain remain largely unexplored. We combined whole-cell electrophysiological recordings with laser-scanning photostimulation to test whether peripheral nerve injury in the spinal nerve ligation (SNL) mouse model of neuropathic pain leads to alterations in the functional connectivity of spinal cord circuits including lamina II excitatory interneurons. Here we show that SNL enhances excitation and decreases inhibition to lamina II excitatory interneurons along with their increased glutamate-evoked excitability. The enhanced excitatory postsynaptic input and connectivity evoked by SNL eventually return to normal levels concurrently with the resolution of the neuropathic pain states. The physiological pattern highly correlates with mouse pain behaviors following SNL, supporting a neurophysiological mechanism of central sensitization and neuropathic pain that is functionally localized to the spinal dorsal horn. Together, these data support that SNL induces functional changes in synaptic input and connectivity to lamina II excitatory interneurons that code for pain perception, and thus provide new insights into the mechanism and locus of pain hypersensitivity.

Predictors of prison-based treatment outcomes: a comparison of men and women participants.

The purpose of this study was to examine differences between men and women entering prison-based therapeutic community (TC) treatment and to explore the relationship of those differences to posttreatment outcomes (i.e., aftercare participation and reincarceration rates). Extensive treatment-intake interview data for 4,386 women and 4,164 men from 16 prison-based TCs in California were compared using chi-square analyses and t-tests. Logistic regression analyses were then conducted separately for men and women to identify gender-specific factors associated with post-treatment outcomes. Prison intake data and treatment participation data come from a 5-year process and outcome evaluation of the California Department of Corrections' (CDC) Prison Treatment Expansion Initiative. The return-to-custody data came from the CDC's Offender Based Information System. Bivariate results showed that women were at a substantial disadvantage compared with their male counterparts with regard to histories of employment, substance abuse, psychological functioning, and sexual and physical abuse prior to incarceration. In contrast, men had more serious criminal justice involvement than women prior to incarceration. After controlling for these and other factors related to outcomes, regression findings showed that there were both similarities and differences with regard to gender-specific predictors of posttreatment outcomes. Time in treatment and motivation for treatment were similar predictors of aftercare participation for men and women. Psychological impairment was the strongest predictor of recidivism for both men and women. Substantial differences in background characteristics and the limited number of predictors related to posttreatment outcomes for women suggests the plausibility of gender-specific paths in the recovery process.

One year return to custody rates among co-disordered offenders.

The extent to which therapeutic community (TC) methods meet the treatment needs of offenders with substance abuse disorders and co-occurring psychiatric disorders in prison is largely unknown. Very little research has been conducted with this population. The purposes of this study were to generate profiles of co-disordered drug offenders entering TC treatment in prison and to assess their post-release reincarceration rates, compared with drug offenders without psychiatric disorders. Extensive intake interview data for over 8,500 men and women who received treatment in one of 16 prison-based TCs in California were analyzed to produce profiles of co-disordered participants. Intake data come from a 5 year process and outcome evaluation of the California Department of Corrections' (CDC's) treatment initiative. Post-release reincarceration rates come from the CDC's Offender Based Information System. Compared with non-psychiatric disordered drug offenders, co-disordered offenders had substantially more severe substance abuse and criminal histories, in addition to their psychiatric impairment, at treatment entry. Logistic regression results indicated that, compared with drug offenders without psychiatric illness, co-disordered offenders were significantly more likely to be reincarcerated during the first year of their parole. These results suggest that prison treatment programs may need to use more comprehensive diagnostic assessments at intake to assess the diverse mental health needs of drug offenders with co-occurring psychiatric disorders and to develop treatment approaches suitable for this population.