Spatial distribution of vastus lateralis blood flow and oxyhemoglobin saturation measured at the end of isometric quadriceps contraction by multichannel near-infrared spectroscopy.

Muscle blood flow (MBF) and muscle oxygen saturation (SmO(2)) were measured at eight locations (four proximal, four distal) over a 4 x 8 cm(2) area of the vastus lateralis at rest and immediately after isometric, maximal quadriceps contraction using multichannel, frequency-domain, near-infrared spectroscopy. A venous occlusion was applied 20 s before the end of the exercise, so that the venous-occlusion-induced increase in total hemoglobin was recorded without any delay after the end of the exercise. Therefore, we were able to investigate the relationship between the exercise-induced changes in vastus lateralis MBF and SmO(2). After exercise, MBF increased significantly at each measured location. Comparing the MBF values measured at the end of exercise in the proximal and distal regions, we observed that only one proximal region had a significantly higher MBF than the corresponding distal one. The maximum desaturation measured during exercise was positively correlated with the postexercise to pre-exercise MBF ratio in both the proximal (P=0.016) and distal (P=0.0065) regions. These data confirm that frequency-domain tissue oximeters are noninvasive, powerful tools to investigate the spatial and temporal features of muscle blood flow and oxygenation, with potential applications in areas of pathophysiology

A phase 1 trial of SGNâ CD70A in patients with CD70â positive, metastatic renal cell carcinoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148406/1/cncr31912.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148406/2/cncr31912_am.pd

61MO Biomarker analysis of men with enzalutamide (enza)-resistant metastatic castration-resistant prostate cancer (mCRPC) treated with pembrolizumab (pembro) + enza in KEYNOTE-199

Background: In KEYNOTE-199 (NCT02787005), pembro + enza had durable antitumor activity in enza-refractory mCRPC. We evaluated the association between prespecified biomarkers and clinical outcomes. Methods: Cohorts 4 (C4; RECIST-measurable disease) and 5 (C5; nonmeasurable, bone-predominant disease) enrolled men with chemotherapy-naive mCRPC, irrespective of PD-L1 status, that progressed after initial response to enza. We evaluated TMB by whole exome sequencing (n = 64), PD-L1 combined positive score (CPS) by IHC (n = 124), and 18-gene T-cell–inflamed gene expression profile (TcellinfGEP) by NanoString (n = 51). Outcomes were DCR, PFS, PSA response, PSA progression, OS, and ORR per blinded independent review (C4 only). Significance of continuous biomarkers (CPS, TMB, GEP) was prespecified at 0.05 for 1-sided P values from logistic (ORR, DCR, PSA response) and Cox proportional hazard (PFS, OS, PSA progression) regression adjusted for ECOG PS. Results: In C4, ORR was 10% (5/48) in pts with evaluable TMB data and 12% (10/81) in pts with CPS data. In C4 and C5, 16% (10/64) and 14% (17/124) of pts with TMB and CPS data, respectively, achieved a PSA response. TMB was significantly associated with DCR (P = 0.03) and trended toward an association with PSA response (P = 0.08). TMB (AUROC [95% CI]: 0.68 [0.51-0.86]), but not CPS (0.54 [0.41-0.67]) or TcellinfGEP (0.55 [0.37-0.74]), enriched for PSA response. TMB (P = 0.04), but not CPS (P = 0.57) or TcellinfGEP (P = 0.32), was significantly associated with PSA progression. There was 1 MSI-H pt (per Promega PCR assay); this pt achieved an objective and PSA response and had PFS \u3e6 months. TMB, CPS, and TcellinfGEP were not associated with PFS or OS. There was a low prevalence of TMB ≥175 mut/exome (11%) and TcellinfGEP-high (≥−0.318; 16%). Conclusions: In this biomarker analysis of KEYNOTE-199 C4-C5, PD-L1 CPS and TcellinfGEP were not significantly associated with clinical outcome. Despite the low prevalence of TMB ≥175 mut/exome, TMB was positively associated with outcomes of pembro + enza in pts with mCRPC. The sample sizes for the exploratory analyses were small, and results should be interpreted with caution

Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study

PURPOSE: Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population. METHODS: The phase II KEYNOTE-199 study included three cohorts of patients with mCRPC treated with docetaxel and one or more targeted endocrine therapies. Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1-positive and PD-L1-negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression. All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary end point was objective response rate per RECIST v1.1 assessed by central review in cohorts 1 and 2. Secondary end points included disease control rate, duration of response, overall survival (OS), and safety. RESULTS: Two hundred fifty-eight patients were enrolled: 133 in cohort 1, 66 in cohort 2, and 59 in cohort 3. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, = 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%. CONCLUSION: Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging

Secretome-Based Identification of ULBP2 as a Novel Serum Marker for Pancreatic Cancer Detection

BACKGROUND: To discover novel markers for improving the efficacy of pancreatic cancer (PC) diagnosis, the secretome of two PC cell lines (BxPC-3 and MIA PaCa-2) was profiled. UL16 binding protein 2 (ULBP2), one of the proteins identified in the PC cell secretome, was selected for evaluation as a biomarker for PC detection because its mRNA level was also found to be significantly elevated in PC tissues. METHODS: ULBP2 expression in PC tissues from 67 patients was studied by immunohistochemistry. ULBP2 serum levels in 154 PC patients and 142 healthy controls were measured by bead-based immunoassay, and the efficacy of serum ULBP2 for PC detection was compared with the widely used serological PC marker carbohydrate antigen 19-9 (CA 19-9). RESULTS: Immunohistochemical analyses revealed an elevated expression of ULPB2 in PC tissues compared with adjacent non-cancerous tissues. Meanwhile, the serum levels of ULBP2 among all PC patients (n = 154) and in early-stage cancer patients were significantly higher than those in healthy controls (p<0.0001). The combination of ULBP2 and CA 19-9 outperformed each marker alone in distinguishing PC patients from healthy individuals. Importantly, an analysis of the area under receiver operating characteristic curves showed that ULBP2 was superior to CA 19-9 in discriminating patients with early-stage PC from healthy controls. CONCLUSIONS: Collectively, our results indicate that ULBP2 may represent a novel and useful serum biomarker for pancreatic cancer primary screening

Remote supervision in psychiatry training: Unlocking capacity and technology

Objective: This paper explores the literature regarding remote supervision in the context of training in psychiatry with contemporary pedagogic theory and practice and utilising telephonic and videoconference technologies to enhance education outcomes. Conclusion: Remote supervision may provide psychiatry trainees with a balance between autonomy and support, promote clinical and professional independence in addition to developing a specific subset of telehealth skills whilst unlocking supervisory capacity to grow the psychiatry workforce, particularly in rural and remote settings

Pancreatic cancer and personalized medicine: Can genomics facilitate early diagnosis or improve therapeutic outcomes?

Despite recent advances in diagnosis and treatment of certain cancers such as breast, colon and prostate cancers, pancreatic cancer remains a deadly malignancy with a mortality rate almost equal to its incidence. The survival benefit after all possible medical interventions is still disappointing for the majority of patients with pancreatic cancer. Improving the quality of life and increasing survival remain as the key objectives of pharmacogenomics and clinical investigation in pancreatic cancer. There are several notable genetic loci (e.g., RRM1, CDA, DPYD, UGT1A1) known to predict the toxicity of drugs used in pancreatic cancer such as gemcitabine, capecitabine, platinum agents and irinotecan. Other genes are associated with efficacy of these drugs (e.g., HuR, DCK, TS, ERCC1), although prospective validation of their clinical utility is still required. This paper presents the latest research advances in pharmacogenomics of pancreatic cancer with a view to molecular guidance for clinical diagnosis and individualized patient care. © 2010 Bentham Science Publishers Ltd

Redefining hormone resistance in prostate cancer

Prostate cancer relies on signaling through the androgen receptor (AR) for maintenance and progression; and androgen-deprivation therapy remains a cornerstone of treatment for advanced prostate cancer. An effective clinical classification of prostate cancer should account for the extent of the disease as well as the mechanisms that are driving the growth of the tumor. The previous terms hormone-sensitive and hormone-refractory described response to treatment. It has become clear that these terms do not reflect the mechanism of disease relapse; however over the last decade there has been a better understanding of androgen-receptor mediated signaling effects and incomplete suppression of androgens in prostate cancer. The Prostate Cancer Clinical Trials Working Group 2 (PCWG2) now recommends addressing the spectrum of clinical states based on castration status as this ligand-centered terminology can more accurately describe the patients’ disease, and ultimately provides a useful framework for patient management and drug development. Optimized use of androgen-deprivation therapy, low molecular weight inhibitors of adrenal androgen biosynthesis, and new AR antagonists are promising new therapeutics that can further define the meaning of castrate state. As hormone resistance is redefined to include patients that are refractory to treatments that ablate adrenal and in situ tumoral androgens, a meaningful new clinical state in patients will be forged. We propose a model for incorporating these patients into the current PCWG2 conceptualization of the disease