Low Pretreatment CD4+:CD8+ T Cell Ratios and CD39+CD73+CD19+ B Cell Proportions Are Associated with Improved Relapse-Free Survival in Head and Neck Squamous Cell Carcinoma.

The ectonucleotidases CD39 and CD73 are present on immune cells and play important roles in cancer progression by suppressing antitumour immunity. As such, CD39 and CD73 on peripheral blood mononuclear cells (PBMCs) are emerging as potential biomarkers to predict disease outcomes and treatment responses in cancer patients. This study aimed to examine T and B cells, including CD39 and CD73 expressing subsets, by flow cytometry in PBMCs from 28 patients with head and neck squamous cell carcinoma (HNSCC) and to assess the correlation with the treatment modality, human papillomavirus (HPV) status, and relapse-free survival (RFS). The PBMCs were examined pre-, mid-, and post-radiotherapy with concurrent cisplatin chemotherapy or anti-epidermal growth factor receptor antibody (cetuximab) therapy. Combination radiotherapy caused changes to T and B cell populations, including CD39 and CD73 expressing subsets, but no such differences were observed between concurrent chemotherapy and cetuximab. Pretreatment PBMCs from HPV+ patients contained increased proportions of CD39-CD73-CD4+ T cells and reduced proportions of CD39-/+CD73+CD4+ T cells compared to the equivalent cells from HPV- patients. Notably, the pretreatment CD4+:CD8+ T cell ratios and CD39+CD73+CD19+ B cell proportions below the respective cohort medians corresponded with an improved RFS. Collectively, this study supports the notion that CD39 and CD73 may contribute to disease outcomes in HNSCC patients and may assist as biomarkers, either alone or as part of immune signatures, in HNSCC. Further studies of CD39 and CD73 on PBMCs from larger cohorts of HNSCC patients are warranted.

Comparison of peripheral blood mononuclear cell isolation techniques and the impact of cryopreservation on human lymphocytes expressing CD39 and CD73.

CD39 and CD73 are ecto-nucleotidases present on human peripheral blood mononuclear cells (PBMCs) and are emerging biomarkers on these cells in various disorders including cancer. Many factors influence PBMC quality, so it is essential to validate sample processing methods prior to incorporation in clinical studies. This study examined the impact of both PBMC cryopreservation and PBMC isolation using SepMate density gradient centrifugation on CD39 and CD73 expressing subsets. First, PBMCs were isolated from the peripheral blood of 11 healthy donors by routine Ficoll-Paque density gradient centrifugation, cryopreserved and compared with freshly isolated PBMCs by flow cytometry. The proportions of T and B cells expressing combinations of CD39 and CD73 were relatively stable over 6-month cryopreservation, although some T cell combinations revealed small but significant changes. Second, peripheral blood was collected from six healthy donors to compare PBMCs isolated by SepMate or Ficoll-Paque density gradient centrifugation. Compared with Ficoll-Paque, the more rapid SepMate method yielded 9.1% less PBMCs but did not alter cell viability or proportions of T and B cells expressing combinations of CD39 and CD73. The present study reveals that cryopreservation is suitable for studying T and B cells expressing combinations of CD39 and CD73. However, caution should be exercised when observing small differences in these cryopreserved subsets between different cohorts. Further, SepMate and Ficoll-Paque methods of PBMC isolation show similar results for T and B cell subset analysis; however, SepMate is a faster and easier approach.

The urokinase plasminogen activation system in gastroesophageal cancer: A systematic review and meta-analysis.

BACKGROUND: The urokinase plasminogen activation (uPA) system is a crucial pathway for tumour invasion and establishment of metastasis. Although there is good evidence that uPA system expression is a clinically relevant biomarker in some solid tumours, its role in gastroesophageal cancer is uncertain. RESULTS: We identified 22 studies encompassing 1966 patients which fulfilled the inclusion criteria. uPA, uPAR, or PAI-1 expression is significantly associated with high risk clinicopathological features. High uPA expression is associated with a shorter RFS (HR 1.90 95% 1.16-3.11, p = 0.01) and OS (HR 2.21 95% CI 1.74-2.80, p < 0.0001). High uPAR expression is associated with poorer OS (HR 2.21 95%CI 1.82-2.69, p < 0.0001). High PAI-1 expression is associated with shorter RFS (HR 1.96 96% CI 1.07-3.58, p = 0.03) and OS (HR 1.84 95%CI 1.28-2.64, p < 0.0001). There was no significant association between PAI-2 expression and OS (HR 0.97 95%CI 0.48-1.94, p < 0.92) although data was limited. MATERIALS AND METHODS: We undertook a systematic review evaluating expression of uPA, urokinase plasminogen activator receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1/SerpinE1) and plasminogen activator inhibitor-2 (PAI-2/SerpinB2) on primary oesophageal, gastro-oesophageal junction, and gastric adenocarcinomas. We performed a meta-analysis of clinicopathological associations, overall survival (OS) and recurrence free survival (RFS). CONCLUSIONS: We conclude that the uPA system is a clinically relevant biomarker in primary gastroesophageal cancer, with higher expression of uPA, uPAR and PAI-1 associated with higher risk disease and poorer prognosis. This also highlights the potential utility of the uPA system as a therapeutic target for improved treatment strategies.

Development and Feasibility Testing of PROMPT-Care, an eHealth System for Collection and Use of Patient-Reported Outcome Measures for Personalized Treatment and Care: A Study Protocol.

BACKGROUND: Patient-reported outcome (PRO) measures have been used widely to screen for depression, anxiety, and symptoms in cancer patients. Computer-based applications that collect patients' responses and transfer them to the treating health professional in real time have the potential to improve patient well-being and cancer outcomes. OBJECTIVE: This study will test the feasibility and acceptability of a newly developed eHealth system which facilitates PRO data capture from cancer patients, data linkage and retrieval to support clinical decisions and patient self-management, and data retrieval to support ongoing evaluation and innovative research. METHODS: The eHealth system is being developed in consultation with 3 overarching content-specific expert advisory groups convened for this project: the clinical advisory group, technical advisory group, and evaluation advisory group. The following work has already been completed during this phase of the study: the Patient-Reported Outcome Measures for Personalized Treatment and Care (PROMPT-Care) eHealth system was developed, patient-reported outcomes were selected (distress, symptoms, unmet needs), algorithms to inform intervention thresholds for clinical and self-management were determined, clinician PRO feedback summary and longitudinal reports were designed, and patient self-management resources were collated. PROsaiq, a custom information technology system, will transfer PRO data in real time into the hospital-based oncology information system to support clinical decision making. The PROMPT-Care system feasibility and acceptability will be assessed through patients completing PROMPT-Care assessments, participating in face-to-face cognitive interviews, and completing evaluation surveys and telephone interviews and oncology staff participating in telephone interviews. RESULTS: Over the course of 3 months, the system will be pilot-tested with up to 50 patients receiving treatment or follow-up care and 6 oncology staff at 2 hospitals in New South Wales, Australia. Data will be collected to determine the accuracy and completeness of data transfer procedures, extent of missing data from participants' assessments, acceptability of the eHealth system and usefulness of the self-management resources (via patient evaluation surveys and interviews), and acceptability and perceived usefulness of real-time PRO reporting (via oncology staff interviews) at the completion of the pilot phase. CONCLUSIONS: This research investigates implementation of evidence into real world clinical practice through development of an efficient and user-friendly eHealth system. This study of feasibility and acceptability of the newly developed eHealth system will inform the next stage of larger scale testing and future implementation of the system as part of routine care. CLINICALTRIAL: Australian New Zealand Clinical Trials Registry ACTRN1261500135294; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=369299&isReview=true (Archived by WebCite at http://www.webcitation.org/6lzylG5A0).

Beam perturbation characteristics of a 2D transmission silicon diode array, Magic Plate.

The main objective of this study is to demonstrate the performance characteristics of the Magic Plate (MP) system when operated upstream of the patient in trans-mission mode (MPTM). The MPTM is an essential component of a real-time QA system designed for operation during radiotherapy treatment. Of particular interest is a quantitative study into the influence of the MP on the radiation beam quality at several field sizes and linear accelerator potential differences. The impact is measured through beam perturbation effects such as changes in the skin dose and/or percentage depth dose (PDD) (both in and out of field). The MP was placed in the block tray of a Varian linac head operated at 6, 10 and 18 MV beam energy. To optimize the MPTM operational setup, two conditions were investigated and each setup was compared to the case where no MP is positioned in place (i.e., open field): (i) MPTM alone and (ii) MPTM with a thin passive contamination electron filter. The in-field and out-of-field surface doses of a solid water phantom were investigated for both setups using a Markus plane parallel (Model N23343) and Attix parallel-plate, MRI model 449 ionization chambers. In addition, the effect on the 2D dose distribution measured by the Delta4 QA system was also investi-gated. The transmission factor for both of these MPTM setups in the central axis was also investigated using a Farmer ionization chamber (Model 2571A) and an Attix ionization chamber. Measurements were performed for different irradiation field sizes of 5 × 5 cm2 and 10 × 10 cm2. The change in the surface dose relative to dmax was measured to be less than 0.5% for the 6 MV, 10 MV, and 18 MV energy beams. Transmission factors measured for both set ups (i & ii above) with 6 MV, 10 MV, and 18 MV at a depth of dmax and a depth of 10 cm were all within 1.6% of open field. The impact of both the bare MPTM and the MPTM with 1 mm buildup on 3D dose distribution in comparison to the open field investigated using the Delta4 system and both the MPTM versions passed standard clinical gamma analysis criteria. Two MPTM operational setups were studied and presented in this article. The results indicate that both versions may be suitable for the new real-time megavoltage photon treatment delivery QA system under development. However, the bare MPTM appears to be slightly better suited of the two MP versions, as it minimally perturbs the radiation field and does not lead to any significant increase in skin dose to the patient.

Gastric cancer stem cells: evidence, potential markers, and clinical implications.

Gastric cancer is a significant global health problem. It is the fifth most common cancer and third leading cause of cancer-related death worldwide (Torre et al. in CA Cancer J Clin 65(2):87-108, 2015). Despite advances in treatment, overall prognosis remains poor, due to tumour relapse and metastasis. There is an urgent need for novel therapeutic approaches to improve clinical outcomes in gastric cancer. The cancer stem cell (CSC) model has been proposed to explain the high rate of relapse and subsequent resistance of cancer to current systemic treatments (Vermeulen et al. in Lancet Oncol 13(2):e83-e89, 2012). CSCs have been identified in many solid malignancies, including gastric cancer, and have significant clinical implications, as targeting the CSC population may be essential in preventing the recurrence and spread of a tumour (Dewi et al. in J Gastroenterol 46(10):1145-1157, 2011). This review seeks to summarise the current evidence for CSC in gastric cancer, with an emphasis on candidate CSC markers, clinical implications, and potential therapeutic approaches.

A method for measuring tissue-equivalent dose using a pin diode and activation foil in epithermal neutron beams with EN < 100 keV.

Silicon (Si) pin diodes can be used for neutron dosimetry by observing the change in forward bias voltage caused by neutron induced displacement damage in the diode junction. Pin diode energy response depends on Si displacement damage KERMA (K(Si)). It is hypothesised that tissue-equivalent (TE) neutron dose could be expressed as a linear combination of K(Si) and foil activation terms. Monte Carlo simulations (MCNP) of parallel monoenergetic neutron beams incident on a cylindrical TE phantom were used to calculate TE dose, K(Si) and Au, Cu and Mn foil activations along the central axis of the phantom. For spectra with neutron energies <100 keV, it is possible to estimate the TE kerma based on silicon damage kerma and Cu or Mn foil measurements. More accurate estimates are possible for spectra where the maximum neutron energy does not exceed 30 keV.

What happens after a lung scan? Management and outcome of patients in a regional hospital.

Pulmonary embolism (PE) remains a common preventable cause of death in hospitalized patients. The purpose of this study is to examine the in-hospital management, complications of treatment and clinical outcomes of inpatients undergoing lung scintigraphy for the diagnosis of PE in a regional hospital. Two hundred consecutive inpatients with suspected PE were enrolled. The results of lung scans, stratified according to the probability of pulmonary embolism, were correlated with anticoagulation status, discharge diagnosis, haemorrhagic complications and clinical outcome at 6 months. The use of complementary imaging investigations was also determined. Other imaging was performed infrequently (Doppler ultrasound in 18% of patients, CT pulmonary angiography (CT-PA) in 0.5% and conventional pulmonary angiography in 4% of patients). Long-term anticoagulation was initiated in 66 patients (33%), including 10 with intermediate probability lung scans (IPLS) who had no further investigations. Major haemorrhage occurred in 14% of all long-term anticoagulated patients followed up. The recognized recurrence rate was very low (3%) and there was no documented mortality from PE. Most patients with suspected PE are treated on the basis of the lung scan result without further tests. However, other imaging (especially CT-PA and conventional pulmonary angiography) should be performed prior to anticoagulation in patients with IPLS in whom the diagnosis is in doubt. Standard anticoagulation for 6 months appears to be effective for PE, and the recurrence rate is low. However, it has a significant risk of major haemorrhagic complications.

Gallium avid breast carcinoma.

Primary breast carcinomas are generally thallium (Tl-201) avid but uncommonly accumulate gallium (GA-67). Therefore, GA-67 scans are not routinely performed in patients with suspected breast cancer. We report a rare case of a primary breast carcinoma with bone marrow metastases where the primary lesion was GA-67 avid but did not accumulate Tl-201. The case also illustrated an unusual presentation of aggressive metastatic breast adenocarcinoma with pancytopenia or bone marrow failure. The extensive bone marrow metastases of the primary breast carcinoma were evident on both the Tl-201 and GA-67 scans.