Satisfaction With Clinician-Led Germline Genetic Counseling in Patients With Prostate Cancer.

PURPOSE: Indications for germline testing in prostate cancer patients have expanded substantially over the past decade. With a near-universal shortage of genetic counselors and increasing demand, increased access to genetic counseling is crucial. We sought to prospectively implement and assess a clinician-led approach to genetic counseling and testing. MATERIALS AND METHODS: Patients with metastatic or localized prostate cancer meeting National Comprehensive Cancer Network® criteria for consideration of genetic testing were offered pre-test genetic counseling by their urologist or medical oncologist as part of their routine clinical care and concurrently approached for enrollment in the Germline Genetics in Prostate Cancer Study. Consented patients filled out a post-counseling survey using validated instruments to assess the quality of counseling. For patients who elected to undergo genetic testing, an additional validated questionnaire was completed following disclosure of results. The primary outcome was the proportion of patients undergoing testing, with a target >60% of patients. The secondary outcome was overall satisfaction with counseling, with a target >85% of patients. RESULTS: A total of 275 patients enrolled, and 203 patients elected to undergo genetic testing. Post-counseling surveys were obtained from 265 patients, and post-genetic testing surveys were obtained from 132 patients. Patient satisfaction was high, with 98% of patients reporting being satisfied with the overall quality of pre-test counseling, and 74% of patients elected to undergo genetic testing. CONCLUSIONS: These results support the effectiveness of clinician-led genetic counseling in prostate cancer. With clinician training, this approach can be utilized to expand access to appropriate germline genetic testing.

Initial Findings from a High Genetic Risk Prostate Cancer Clinic.

OBJECTIVE: To improve prostate cancer screening for high-risk men, we developed an early detection clinic for patients at high genetic risk of developing prostate cancer. Despite the rapidly growing understanding of germline variants in driving aggressive prostate cancer and the increased availability of genetic testing, there is little evidence surrounding how best to screen these men. METHODS: We are reporting on the first 45 patients enrolled, men between the ages of 35-75, primarily with known pathogenic germline variants in prostate cancer susceptibility genes. Screening consists of an intake lifestyle survey, PSA, DRE, and SelectMDx urine assay. A biopsy was recommended for any of the following indications: 1) abnormal DRE, 2) PSA above threshold, or 3) SelectMDx above threshold. The primary outcomes were number needed to screen, and number needed to biopsy to diagnose a patient with prostate cancer. RESULTS: Patients enrolled in the clinic included those with BRCA1 (n=7), BRCA2 (n=16), Lynch Syndrome (n=6), and CHEK2 (n = 4) known pathogenic germline variants. The median age and PSA were 58 (range 35-71) and 1.4 ng/ml (range 0.1-11.4 ng/ml), respectively. 12 patients underwent a prostate needle biopsy and there were 4positive biopsies for prostate cancer. CONCLUSION: These early data support the feasibility of opening a dedicated clinic for men at high genetic risk of prostate cancer. This early report on the initial enrollment of our long-term study will help optimize early detection protocols and provide evidence for personalized prostate cancer screening in men with key pathogenic germline variants.

Effect of exercise on neuromuscular toxicity in oxaliplatin-treated mice.

INTRODUCTION/AIMS: Clinically, the chemotherapeutic agent oxaliplatin can cause peripheral neuropathy, impaired balance, and muscle wastage. Using a preclinical model, we investigated whether exercise intervention could improve these adverse conditions. METHODS: Mice were chronically treated with oxaliplatin alone or in conjunction with exercise. Behavioral studies, including mechanical allodynia, rotarod, open-field, and grip-strength tests, were performed. After euthanasia, multiple organs and four different muscle types were dissected and weighed. The cross-sectional area (CSA) of muscle fibers in the gastrocnemius muscle was assessed and gene expression analysis performed on the forelimb triceps muscle. RESULTS: Oxaliplatin-treated mice displayed reduced weight gain, mechanical allodynia, and exploratory behavior deficits that were not significantly improved by exercise. Oxaliplatin-treated exercised mice showed modest evidence of reduced muscle wastage compared with mice treated with oxaliplatin alone, and exercised mice demonstrated evidence of a mild increase in CSA of muscle fibers. DISCUSSION: Exercise intervention did not improve signs of peripheral neuropathy but moderately reduced the negative impact of oxaliplatin chemotherapy related to muscle morphology, suggesting the potential for exploring the impact of exercise on reducing oxaliplatin-induced neuromuscular toxicity in cancer patients.

Oxaliplatin-induced haematological toxicity and splenomegaly in mice.

PURPOSE: Haematological toxicities occur in patients receiving oxaliplatin. Mild anaemia (grade 1-2) is a common side effect and approximately 90% of recipients develop measurable spleen enlargement. Although generally asymptomatic, oxaliplatin-induced splenomegaly is independently associated with complications following liver resection for colorectal liver metastasis and separately with poorer patient outcomes. Here, we investigated oxaliplatin-induced haematological toxicities and splenomegaly in mice treated with escalating dosages comparable to those prescribed to colorectal cancer patients. METHODS: Blood was analysed, and smears assessed using Wright-Giemsa staining. Paw coloration was quantified as a marker of anaemia. Spleen weight and morphology were assessed for abnormalities relating to splenomegaly and a flow cytometry and multiplex cytokine array assessment was performed on splenocytes. The liver was assessed for sinusoidal obstructive syndrome. RESULTS: Blood analysis showed dose dependent decreases in white and red blood cell counts, and significant changes in haematological indices. Front and hind paws exhibited dose dependent and dramatic discoloration indicative of anaemia. Spleen weight was significantly increased indicating splenomegaly, and red pulp tissue exhibited substantial dysplasia. Cytokines and chemokines within the spleen were significantly affected with temporal upregulation of IL-6, IL-1α and G-CSF and downregulation of IL-1ß, IL-12p40, MIP-1ß, IL-2 and RANTES. Flow cytometric analysis demonstrated alterations in splenocyte populations, including a significant reduction in CD45+ cells. Histological staining of the liver showed no evidence of sinusoidal obstructive syndrome but there were signs suggestive of extramedullary haematopoiesis. CONCLUSION: Chronic oxaliplatin treatment dose dependently induced haematological toxicity and splenomegaly characterised by numerous physiological and morphological changes, which occurred independently of sinusoidal obstructive syndrome.

Dorsal root ganglion explants derived from chemotherapy-treated mice have reduced neurite outgrowth in culture.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and debilitating adverse effect of cancer therapy that results from treatment with neurotoxic agents. Although chemotherapy treatment has been shown to inhibit neurite outgrowth from dorsal root ganglion (DRG) neurons in vitro, evidence for this effect in vivo is lacking. In this study, we investigated whether chemotherapy treatment in mice alters the capacity for axonal outgrowth from ex vivo cultured DRG explants. Using a neurite outgrowth assay, we demonstrated that DRG explants isolated at day 30 from mice treated with 6 cycles of paclitaxel, or 12 cycles of oxaliplatin showed a significant reduction in neurite outgrowth as compared to DRG explants from control vehicle-treated mice. DRGs that were isolated at day 90 showed recovery of the neurite outgrowth, and no significant differences were detected in comparison to vehicle controls. These results are corroborated with an in vitro model, whereby direct application of oxaliplatin and paclitaxel dose-dependently reduced neurite outgrowth of DRG explants. In conclusion, our results show that the effect of paclitaxel and oxaliplatin on the structural plasticity of DRG is retained ex vivo (for at least 30 days) and suggest the use of DRG explants derived from chemotherapy-treated mice as an efficient method to investigate the mechanisms underlying CIPN and test for possible therapeutic targets.

Triheptanoin Protects Motor Neurons and Delays the Onset of Motor Symptoms in a Mouse Model of Amyotrophic Lateral Sclerosis.

There is increasing evidence that energy metabolism is disturbed in Amyotrophic Lateral Sclerosis (ALS) patients and animal models. Treatment with triheptanoin, the triglyceride of heptanoate, is a promising approach to provide alternative fuel to improve oxidative phosphorylation and aid ATP generation. Heptanoate can be metabolized to propionyl-CoA, which after carboxylation can produce succinyl-CoA and thereby re-fill the tricarboxylic acid (TCA) cycle (anaplerosis). Here we tested the hypothesis that treatment with triheptanoin prevents motor neuron loss and delays the onset of disease symptoms in female mice overexpressing the mutant human SOD1G93A (hSOD1G93A) gene. When oral triheptanoin (35% of caloric content) was initiated at P35, motor neuron loss at 70 days of age was attenuated by 33%. In untreated hSOD1G93A mice, the loss of hind limb grip strength began at 16.7 weeks. Triheptanoin maintained hind limb grip strength for 2.8 weeks longer (p<0.01). Loss of balance on the rotarod and reduction of body weight were delayed by 13 and 11 days respectively (both p<0.01). Improved motor function occurred in parallel with alterations in the expression of genes associated with muscle metabolism. In gastrocnemius muscles, the mRNA levels of pyruvate, 2-oxoglutarate and succinate dehydrogenases and methyl-malonyl mutase were reduced by 24-33% in 10 week old hSOD1G93A mice when compared to wild-type mice, suggesting that TCA cycling in skeletal muscle may be slowed in this ALS mouse model at a stage when muscle strength is still normal. At 25 weeks of age, mRNA levels of succinate dehydrogenases, glutamic pyruvic transaminase 2 and the propionyl carboxylase ß subunit were reduced by 69-84% in control, but not in triheptanoin treated hSOD1G93A animals. Taken together, our results suggest that triheptanoin slows motor neuron loss and the onset of motor symptoms in ALS mice by improving TCA cycling.