Oxaliplatin-Induced Neuropathy in Colorectal Cancer

Oxaliplatin use in palliative and adjuvant treatment of colon cancer is frequently limited by cumulative neurotoxicity, leading to reduced quality of life and decreased dose. The mechanism of this neurotoxicity is unclear, but may relate to neuronal voltage-gated sodium channels involving calcium chelation by a metabolite of the drug. Various preventative measures have been tested to reduce the incidence of neurotoxicity, including calcium and magnesium infusions, dose interruption of the drug, and prophylactic neuromodulatory agents. Despite the promising efficacy of these measures, they are not universally accepted. Less is known about the best way to treat established neurotoxicity, which is permanent in some patients, although venlafaxine has shown promise in small clinical trials. This paper analyzes the extent, cause and risk factors for neuropathy, and the potential preventative and therapeutic treatments for oxaliplatin-induced neuropathy

Prospective, multisite, international comparison of \u3csup\u3e18\u3c/sup\u3eF-fluoromethylcholine PET/CT, multiparametric MRI, and \u3csup\u3e68\u3c/sup\u3eGa-HBED-CC PSMA-11 PET/CT in men with high-risk features and biochemical failure after radical prostatectomy: Clinical performance and patient outcomes

A significant proportion of men with rising prostate-specific antigen (PSA) levels after radical prostatectomy (RP) fail prostate fossa (PF) salvage radiation treatment (SRT). This study was done to assess the ability of F-fluoromethylcholine ( F-FCH) PET/CT (hereafter referred to as F-FCH), Ga-HBED-CC PSMA-11 PET/CT (hereafter referred to as PSMA), and pelvic multiparametric MRI (hereafter referred to as pelvic MRI) to identify men who will best benefit from SRT. Methods: Prospective, multisite imaging studies were carried out in men who had rising PSA levels after RP, high-risk features, and negative/equivocal conventional imaging results and who were being considered for SRT. F-FCH (91/91), pelvic MRI (88/91), and PSMA (31/91) (Australia) were all performed within 2 wk. Imaging was interpreted by experienced local/central interpreters who were masked with regard to other imaging results, with consensus being reached for discordant interpretations. Expected management was documented before and after imaging, and data about all treatments and PSA levels were collected for 3 y. The treatment response to SRT was defined as a reduction in PSA levels of .50% without androgen deprivation therapy. Results: The median Gleason score, PSA level at imaging, and PSA doubling time were 8, 0.42 (interquartile range, 0.29–0.93) ng/mL, and 5.0 (interquartile range, 3.3–7.6) months. Recurrent prostate cancer was detected in 28% (25/88) by pelvic MRI, 32% (29/91) by F-FCH, and 42% (13/31) by PSMA. This recurrence was found within the PF in 21.5% (19/88), 13% (12/91), and 19% (6/31) and at sites outside the PF (extra-PF) in 8% (7/88), 19% (17/91), and 32% (10/31) by MRI, F-FCH, and PSMA, respectively (P, 0.004). A total of 94% (16/17) of extra-PF sites on F-FCH were within the pelvic MRI field. Intra-pelvic extra-PF disease was detected in 90% (9/10) by PSMA and in 31% (5/16) by MRI. F-FCH changed management in 46% (42/91), and MRI changed management in 24% (21/88). PSMA provided additional management changes over F-FCH in 23% (7/31). The treatment response to SRT was higher in men with negative results or disease confined to the PF than in men with extra-PF disease ( F-FCH 73% [32/44] versus 33% [3/9] [P, 0.02], pelvic MRI 70% [32/46] versus 50% [2/4] [P was not significant], and PSMA 88% [7/ 8] versus 14% [1/7] [P, 0.005]). Men with negative imaging results (MRI, F-FCH, or PSMA) had high (78%) SRT response rates. Conclusion: F-FCH and PSMA had high detection rates for extra-PF disease in men with negative/equivocal conventional imaging results and rising PSA levels after RP. These findings affected management and treatment responses, suggesting an important role for PET in triaging men being considered for curative SRT. 18 18 18 68 18 18 18 18 18 18 18 18 1

Influence of molecular imaging on patient selection for treatment intensification prior to salvage radiation therapy for prostate cancer: a post hoc analysis of the PROPS trial

Background: The impact of molecular imaging (MI) on patient management after biochemical recurrence (BCR) following radical prostatectomy has been described in many studies. However, it is not known if MI-induced management changes are appropriate. This study aimed to determine if androgen deprivation therapy (ADT) management plan is improved by MI in patients who are candidates for salvage radiation therapy. / Methods: Data were analyzed from the multicenter prospective PROPS trial evaluating PSMA/Choline PET in patients being considered for salvage radiotherapy (sRT) with BCR after prostatectomy. We compared the pre- and post-MI ADT management plans for each patient and cancer outcomes as predicted by the MSKCC nomogram. A higher percentage of predicted BCR associated with ADT treatment intensification after MI was considered as an improvement in a patient’s management. / Results: Seventy-three patients with a median PSA of 0.38 ng/mL were included. In bivariate analysis, a positive finding on MI (local or metastatic) was associated with decision to use ADT with an odds ratio of 3.67 (95% CI, 1.25 to 10.71; p = 0.02). No factor included in the nomogram was associated with decision to use ADT. Also, MI improved selection of patients to receive ADT based on predicted BCR after sRT : the predicted nomogram 5-year biochemical-free survivals were 52.5% and 43.3%, (mean difference, 9.2%; 95% CI 0.8 to 17.6; p = 0.03) for sRT alone and ADT±sRT subgroups, while there was no statistically significant difference between subgroups before MI. / Conclusions: PSMA and/or Choline PET/CT before sRT can potentially improve patient ADT management by directing clinicians towards more appropriate intensification

The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial.

Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3+ non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2+ tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268

A Phase 2, Multicenter, Open-Label Study of Anti-Lag-3 Ieramilimab in Combination With Anti-Pd-1 Spartalizumab in Patients With Advanced Solid Malignancies

Ieramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated). Patients received ieramilimab (400 mg) followed by spartalizumab (300 mg) every 3 weeks. The primary endpoint was objective response rate (ORR), along with safety, pharmacokinetics, and biomarker assessments. Of 235 patients, 142 were naive to anti-PD-1/L1 and 93 were pretreated with anti-PD-1/L1 antibodies. Durable responses (\u3e24 months) were seen across all indications for patients naive to anti-PD-1/L1 and in melanoma and RCC patients pretreated with anti-PD1/L1. The most frequent study drug-related AEs were pruritus (15.5%), fatigue (10.6%), and rash (10.6%) in patients naive to anti-PD-1/L1 and fatigue (18.3%), rash (14.0%), and nausea (10.8%) in anti-PD-1/L1 pretreated patients. Biomarker assessment indicated higher expression of T-cell-inflamed gene signature at baseline among responding patients. Response to treatment was durable (\u3e24 months) in some patients across all enrolled indications, and safety findings were in accordance with previous and current studies exploring LAG-3/PD-1 blockade

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Molecular determinants of therapeutic response to targeted therapies in metastatic colorectal cancer

© 2011 Dr. Andrew James WeickhardtGiven the high cost, optimizing survival of patients with colorectal cancer requires research into two important questions. Firstly, can there be improved efficacy of these agents by using novel combinations with existing or other new drugs? Secondly, what are the mechanisms of both innate and acquired resistance to these drugs? Restricting use from those patients who have factors that govern immediate innate resistance will enrich and maximise initial response rates (RR). Identification of mechanisms governing acquired resistance may allow novel future strategies to avoid these mechanisms and allow ongoing durable responses to therapy. This thesis aims to explore methods of optimizing the targeted treatment of the EGFR pathway and the VEGF related pathway in colorectal cancer. The biology of each pathway will be reviewed. Therapeutic options for inhibiting these pathways in colorectal cancer will be discussed, focusing on targeted agents. The concept of maximising the effect of targeting the EGFR pathway by using two drugs that target the same pathway will be reviewed. Additionally, biological characteristics of the tumour that may predict resistance and response to targeting each individual pathway will also be reviewed

Mechanisms of acquired resistance to fibroblast growth factor receptor targeted therapy

Oncogenic activation of the fibroblast growth factor receptor (FGFR) through mutations and fusions of the FGFR gene occur in a variety of different malignancies such as urothelial carcinoma and cholangiocarcinoma. Inhibition of the kinase domain of the FGFR with targeted oral FGFR inhibitors has been shown in both preclinical and early phase clinical trials to lead to meaningful reductions in tumour size and larger confirmatory randomized trials are underway. Acquired resistance to FGFR inhibition using a variety of mechanisms that includes, activation of alternate signaling pathways and expansion of tumour clones with gatekeeper mutations in the FGFR gene. This review summarizes the acquired resistance mechanisms to FGFR therapy and therapeutic approaches to circumventing resistance