Predictors of Unplanned Hospitalizations Among Older Adults Receiving Cancer Chemotherapy.

PURPOSE: Hospitalizations during cancer treatment are costly, can impair quality of life, and negatively affect therapy completion. Our objective was to identify risk factors for unplanned hospitalization among older adults receiving chemotherapy. METHODS: This is a secondary analysis of a multisite cohort study (N = 750) of patients ≥ 65 years of age evaluated with a geriatric assessment (GA) to predict chemotherapy toxicity. The primary outcome of this analysis was unplanned hospitalizations during treatment; the secondary outcome was length of stay (LOS) of the first hospitalization. Independent variables included pretreatment GA measures, laboratory values, cancer type and stage, and treatment intensity characteristics. We used logistic regression to estimate the odds of hospitalization and generalized linear models for LOS in multivariable analyses. RESULTS: The sample median age was 72 years (range, 65-94 years); 59% had stage IV disease. At least one unplanned hospitalization occurred in 193 patients (25.7%) during receipt of chemotherapy. In multivariable analyses controlling for cancer type, the following baseline characteristics were significantly associated with increased odds of hospitalization: needing help bathing or dressing (odds ratio [OR], 1.8; 95% CI, 1.0 to 3.1), polypharmacy (≥ 5 meds) (OR, 1.6; 95% CI, 1.1 to 2.4), more comorbid conditions (OR, 1.1; 95% CI, 1.0 to 1.3), availability of someone to take them to the doctor (OR, 2.0; 95% CI, 1.0 to 4.1), CrCl < 60 mL/min (OR, 1.7; 95% CI, 1.1 to 2.4), and albumin < 3.5 g/dL (OR, 1.8; 95% CI, 1.2 to 2.8). In multivariable analyses, older age, self-reported presence of liver or kidney disease, living alone and depressive symptoms were associated with longer LOS. CONCLUSION: Readily available GA variables and laboratory data, but not age, were associated with unplanned hospitalizations among older adults receiving chemotherapy. If validated, these data can inform prediction models and the design of interventions to decrease unplanned hospitalizations.

Programmed Death 1 and Programmed Death Ligand 1 Inhibitors in Advanced and Recurrent Urothelial Carcinoma: Meta-analysis of Single-Agent Studies.

We performed a systematic review and meta-analysis on the response rates of patients with treatment-refractory urothelial carcinoma treated with programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors. We reviewed the literature for prospective studies evaluating PD-1/PD-L1 inhibitors in refractory urothelial carcinoma patients, which formed the basis for US Food and Drug Administration approval of 5 different antagonistic antibodies targeting PD-1 or PD-L1 (atezolizumab, durvalumab, avelumab, nivolumab, and pembrolizumab). We considered studies examining PD-1/PD-L1-treated patients, which we identified using the following key terms in the Pubmed, Scopus, Web of Science, ClinicalTrial.gov, and Cochrane Library databases. Eligible studies had ≥ 20 patients each and reported response rates, duration of response, and overall survival (OS). We performed fixed and random-effects meta-analyses to model the point estimates for objective response rate and complete response. The median progression-free survival (PFS) and OS for studies reporting these statistics were evaluated. We found 10 eligible studies that met our inclusion criteria, providing extractable numerators and denominators for response rates, PFS, and OS for 1934 patients with metastatic urothelial carcinoma. The objective response rate was 18% (95% confidence interval, 15-22) for second-line or later therapies. The random-effects estimate for complete response was 4% (95% confidence interval, 3-5), including all disease locations and all PD-1 and PD-L1 inhibitors. Median OS and PFS were < 13 months and 3 months, respectively, across all studies, irrespective of PD-L1 expression. We found that the estimated response rates of agents included in this meta-analysis seem to be more favorable than other salvage therapies.

Parity-time-symmetry-breaking gyroscopes: lasing without gain and subthreshold regimes.

We show that the lasing threshold for two coupled resonators (CRs) corresponds to lasing without gain (LWG), a phenomenon analogous to lasing without inversion in atomic systems, when parity-time (PT) symmetry is broken. The use of LWG for gyroscopes may resolve some of the difficulties associated with PT-symmetric gyroscopes. In particular, we find that PT-symmetric systems suffer from undamped Rabi oscillations, whereas LWG systems are overdamped. In addition, observation of enhanced sensitivity should be more straightforward in LWG gyros because the enhancement remains above unity even at couplings far from the exceptional point (EP). Finally, LWG gyros operate more like conventional laser gyroscopes with one frequency for each output direction, and therefore there is no ambiguity in the direction of rotation. Gain saturation in CR systems is found to dramatically boost the size of the sensitivity enhancement, eliminate the Rabi oscillations, and enlarge the parameter space around the EP over which the enhancement is expected to occur. A second situation with broken symmetry is also examined: CR systems below threshold. Whereas the pole in sensitivity coincides with the EP at threshold, the pole can occur far away from the EP for subthreshold systems. Our analysis also puts previous results on passive and active fast-light cavities using atomic vapor cells into the context of EP-enhanced sensing with non-Hermitian Hamiltonians.

Variation in the Thoroughness of Pathologic Assessment and Response Rates of Locally Advanced Rectal Cancers After Chemoradiation.

BACKGROUND: Pathologic complete response (pCR) is associated with better prognosis and guides management for patients with advanced rectal cancer. Response rates vary between series for unclear reasons. We examine whether the thoroughness of pathologic assessment explains differences in pCR rates. METHODS: We retrospectively reviewed pathology reports from patients with stage II/III rectal cancer who underwent chemoradiation and resection in a prospective, multicenter trial. We utilized a novel measure for the thoroughness of pathologic assessment by dividing residual tumor size by the number of cassettes evaluated (tumor size to cassette ratio, TSCR), and evaluated whether TSCR is associated with pCR. We validated our findings using a separate cohort. RESULTS: From the trial cohort, 71 of 247 (29%) patients achieved pCR. The pCR rate ranged from 0 to 45% and mean TSCR ranged 0.29 to 0.87 across 12 institutions. Within each institution, a lower TSCR was associated with pCR, demonstrating a higher degree of thoroughness used for tumors that achieved pCR. Moreover, across all samples, low TSCR was independently associated with pCR on multivariable analysis. This finding was corroborated in a separate cohort of 201 tumors evaluated by five pathologists; each pathologist had a lower mean TSCR for pCR calls compared with non-pCR calls. However, the mean TSCR for an institution was not associated with its overall pCR rate. CONCLUSIONS: Pathologists assess rectal cancers that have responded significantly to neoadjuvant therapy more thoroughly. Thoroughness does not appear to explain differences in pCR rates between institutions. Our results suggest pCR is not a sampling artifact.

Closed-loop superluminal passive cavity.

We demonstrate the operation of a closed-loop fast-light cavity that allows rapid (~10 ms) measurements of the cavity mode frequency and its uncertainty. We vary the scale factor by temperature tuning the atomic density of an intracavity vapor cell. The cavity remains locked even as the system passes through the critical anomalous dispersion where a pole is observed in the scale factor. Positive and negative scale-factor enhancements as large as |S| ≈70 were obtained. To our knowledge, these are the first experiments that demonstrate a scale-factor enhancement in a closed-loop fast-light device by changing the optical path length, laying the groundwork for the improvement of cavity-based metrology instruments such as optical gyroscopes.

Coping strategies, trajectories, and their associations with patient-reported outcomes among women with ovarian cancer.

OBJECTIVE: Most women with ovarian cancer present with advanced stage disease and face aggressive treatments, recurrence, and possible death, yet little is known about how they cope. Our objective was to identify coping strategies used by women with ovarian cancer and their trajectories of use after diagnosis and to assess if coping trajectories are associated with subsequent anxiety, depression, or quality of life. METHODS: Women with ovarian cancer completed questionnaires including the Brief-COPE, HADS, and FACT at 3, 6, and 9 months after diagnosis and the HADS and FACT at 12 months. Using data from 634 women who completed the 3-month questionnaire, factor analysis was conducted to identify coping strategy clusters. Trajectory modeling was used to assess patterns of coping over time. Associations between coping trajectory from 3 to 9 months and patient-reported outcomes at 12 months were investigated using general linear models. RESULTS: Three coping strategy clusters were identified. Use of "taking action/positive framing" followed four distinct trajectories over time: low-stable (44%), medium-stable (32%), medium-decreasing (11%), high-stable (12%). Use of "social/emotional support" had four trajectories: low-increasing (7%), low-decreasing (44%), medium-decreasing (40%), and high-stable (8%). Women either "accepted their reality" (26%) or "used some denial" (74%). Women who accepted reality reported significantly less anxiety and depression and better quality of life at 12 months. Women with high-stable use of taking action/positive framing reported less depression. Women with high-stable use of social/emotional support reported better quality of life. CONCLUSIONS: Strategies to assist women with acceptance, action-planning, positive-framing, and maintaining psychosocial support should be considered.

Development of a Multiplexed Microsphere PCR for Culture-Free Detection and Gram-Typing of Bacteria in Human Blood Samples.

Bloodstream infection is a significant clinical problem, particularly in vulnerable patient groups such as those undergoing chemotherapy and bone marrow transplantation. Clinical diagnostics for suspected bloodstream infection remain centered around blood culture (highly variable timing, in the order of hours to days to become positive), and empiric use of broad-spectrum antibiotics is therefore employed for patients presenting with febrile neutropenia. Gram-typing provides the first opportunity to target therapy (e.g., combinations containing vancomycin or teicoplanin for Gram-positives; piperacillin-tazobactam or a carbapenem for Gram-negatives); however, current approaches require blood culture. In this study, we describe a multiplexed microsphere-PCR assay with flow cytometry readout, which can distinguish Gram-positive from Gram-negative bacterial DNA in a 3.5 h time period. The combination of a simple assay design (amplicon-dependent release of Gram-type specific Cy3-labeled oligonucleotides) and the Luminex-based readout (for quantifying each specific Cy3-labeled sequence) opens opportunities for further multiplexing. We demonstrate the feasibility of detecting common Gram-positive and Gram-negative organisms after spiking whole bacteria into healthy human blood prior to DNA extraction. Further development of DNA extraction methods is required to reach detection limits comparable to blood culture.

Absolute versus relative measures of plasma fatty acids and health outcomes: example of phospholipid omega-3 and omega-6 fatty acids and all-cause mortality in women.

PURPOSE: In a well-characterised community-based prospective study, we aimed to systematically assess the differences in associations of plasma omega-3 and omega-6 fatty acid (FA) status with all-cause mortality when plasma FA status is expressed in absolute concentrations versus relative levels. METHODS: In a community sample of 564 women aged 25-75 years in Queensland, Australia, baseline plasma phospholipid FA levels were measured using gas chromatography. Specific FAs analysed were eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, total long-chain omega-3 FAs, linoleic acid, arachidonic acid, and total omega-6 FAs. Levels of each FA were expressed in absolute amounts (µg/mL) and relative levels (% of total FAs) and divided into thirds. Deaths were monitored for 17 years and hazard ratios and 95% confidence intervals calculated to assess risk of death according to absolute versus relative plasma FA levels. RESULT: In total 81 (14%) women died during follow-up. Agreement between absolute and relative measures of plasma FAs was higher in omega-3 than omega-6 FAs. The results of multivariate analyses for risk of all-cause mortality were generally similar with risk tending to inverse associations with plasma phospholipid omega-3 FAs and no association with omega-6 FAs. Sensitivity analyses examining effects of age and presence of serious medical conditions on risk of mortality did not alter findings. CONCLUSIONS: The directions and magnitude of associations with mortality of absolute versus relative FA levels were comparable. However, plasma FA expressed as absolute concentrations may be preferred for ease of comparison and since relative units can be deduced from absolute units.

Medication beliefs predict medication adherence in ambulatory patients with decompensated cirrhosis.

AIM: To investigate the impact of medication beliefs, illness perceptions and quality of life on medication adherence in people with decompensated cirrhosis. METHODS: One hundred adults with decompensated cirrhosis completed a structured questionnaire when they attended for routine outpatient hepatology review. Measures of self-reported medication adherence (Morisky Medication Adherence Scale), beliefs surrounding medications (Beliefs about Medicines Questionnaire), perceptions of illness and medicines (Brief Illness Perception Questionnaire), and quality of life (Chronic Liver Disease Questionnaire) were examined. Clinical data were obtained via patient history and review of medical records. Least absolute shrinkage and selection operator and stepwise backwards regression techniques were used to construct the multivariable logistic regression model. Statistical significance was set at alpha = 0.05. RESULTS: Medication adherence was "High" in 42% of participants, "Medium" in 37%, and "Low" in 21%. Compared to patients with "High" adherence, those with "Medium" or "Low" adherence were more likely to report difficulty affording their medications (P < 0.001), lower perception of treatment helpfulness (P = 0.003) and stronger medication concerns relative to medication necessity beliefs (P = 0.003). People with "Low" adherence also experienced greater symptom burden and poorer quality of life, including more frequent abdominal pain (P = 0.023), shortness of breath (P = 0.030), and emotional disturbances (P = 0.050). Multivariable analysis identified having stronger medication concerns relative to necessity beliefs (Necessity-Concerns Differential ≤ 5, OR = 3.66, 95%CI: 1.18-11.40) and more frequent shortness of breath (shortness of breath score ≤ 3, OR = 3.87, 95%CI: 1.22-12.25) as independent predictors of "Low"adherence. CONCLUSION: The association between "Low" adherence and patients having strong concerns or doubting the necessity or helpfulness of their medications should be explored further given the clinical relevance.

High-precision, accurate optical frequency reference using a Fabry-Perót diode laser.

We show that the optical output of a temperature and current-tuned Fabry-Perót diode laser system, with no external optical feedback and in which the frequency is locked to Doppler-free hyperfine resonances of the 87Rb D2 line, can achieve high frequency stability and accuracy. Experimental results are presented for the spectral linewidth, frequency stability, and frequency accuracy of the source. Although our optical source is limited by a short-term spectral linewidth greater than 2 MHz, beat signal measurements from two such sources demonstrate a frequency stability of 1.1 kHz, or minimum Allan deviation of 4×10-12, at an integration time τ=15 s and with a frequency accuracy of 60 kHz at τ=300 s. We demonstrate the use of the optical source for the precision measurement of hyperfine level frequency spacings in the 5P3∕2 excited state of 87Rb and provide an accurate frequency scale for optical spectroscopy.

Patient-oriented education and medication management intervention for people with decompensated cirrhosis: study protocol for a randomized controlled trial.

BACKGROUND: People with decompensated cirrhosis require complex medical care and are often prescribed an intricate and frequently changing medication and lifestyle regimen. However, many patients mismanage their medications or have poor comprehension of their disease and self-management tasks. This can lead to harm, hospitalization, and death. METHODS/DESIGN: A patient-oriented education and medication management intervention has been developed for implementation at a tertiary hospital hepatology outpatient center in Queensland, Australia. Consenting patients with decompensated cirrhosis will be randomly allocated to education intervention or usual care treatment arms when they attend routine follow-up appointments. In the usual care arm, participants will be reviewed by their hepatologist according to the current model of care in the hepatology clinic. In the intervention arm, participants will be reviewed by a clinical pharmacist to receive the education and medication management intervention at baseline in addition to review by their hepatologist. Intervention participants will also receive three further educational contacts from the clinical pharmacist within the following 6-month period, in addition to routine hepatologist review that is scheduled within this time frame. All participants will be surveyed at baseline and follow-up (approximately 6 months post-enrollment). Validated questionnaire tools will be used to determine participant adherence, medication beliefs, illness perceptions, and quality of life. Patients' knowledge of dietary and lifestyle modifications, their current medications, and other clinical data will be obtained from the survey, patient interview, and medical records. Patient outcome data will be collected at 52 weeks. DISCUSSION: The intervention described within this protocol is ready to adapt and implement in hepatology ambulatory care centers globally. Investigation of potentially modifiable variables that may impact medication management, in addition to the effect of a clinical pharmacist-driven education and medication management intervention on modifying these variables, will provide valuable information for future management of these patients. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry identifier: ACTRN12616000780459 . Registered on 15 June 2016.

Implementation of a School-Based Educational Program to Increase Breast Cancer Awareness and Promote Intergenerational Transmission of Knowledge in a Rural Mexican Community.

BACKGROUND: Rural women have limited access to breast cancer education, which partially contributes to late diagnosis and treatment. In this pilot study, we tested the feasibility of implementing a school-based breast cancer educational program for adolescents in a rural Mexican community. We hypothesized that the adolescents' knowledge on breast cancer would increase as a result of the program, and that there would be intergenerational transmission of that knowledge to their older female relatives. MATERIALS AND METHODS: Female adolescents from a rural middle school received the educational program. The program would be considered feasible and acceptable if more than 75% reported being satisfied with its contents. Changes in knowledge in the students and their relatives were evaluated using baseline and 4 months follow-up questionnaires. RESULTS: One hundred twenty-six students were enrolled. The program was considered acceptable by 96% of the participants. The students' knowledge regarding breast cancer increased significantly from baseline to 4 months follow-up (63% to 82%). One hundred ninety-four female relatives completed the initial knowledge questionnaires. The relatives' knowledge regarding breast cancer showed a significant increase from baseline to 4 months follow-up (55% to 61%). CONCLUSION: Implementing breast cancer educational programs for adolescents in rural communities is feasible and acceptable. The program increased the adolescents' knowledge on breast cancer, and promoted the intergenerational transmission of that knowledge to their female relatives. Intergenerational transmission of knowledge represents a potential method for providing population-based health awareness education globally. IMPLICATIONS FOR PRACTICE: In limited-resource settings, education is a valuable tool for achieving early detection and downstaging of breast cancer. Unfortunately, rural women lack access to educational opportunities and information about breast cancer, which is a factor contributing to late diagnosis and treatment. In this study, we demonstrated that implementing a school-based breast cancer educational program for female adolescents in a rural Mexican community was feasible, acceptable, and increased their knowledge about breast cancer. Furthermore, the program encouraged the transmission of information to the students' older relatives. Intergenerational transmission of knowledge represents a novel and potentially effective tool in cancer education and promotion.

Oral human papillomavirus infection incidence and clearance: a systematic review of the literature.

Subclinical oral human papillomavirus (HPV) infection that persists for decades is likely to precede an HPV-driven squamous cell carcinoma of the head and neck, but little is known about the natural history of oral HPV. We systematically reviewed and abstracted data from nine manuscripts that examined human immunodeficiency virus-negative and cancer-free subjects for oral HPV DNA to determine the pooled baseline prevalence and incidence of newly acquired oral HPV infections, and specifically for HPV-16. We also documented the clearance rate and the median time to clearance, where data existed. Of 3762 individuals, 7.5 % had an oral infection with any HPV type (1.6 % for HPV-16). Meta-regression analysis estimated the 12-month cumulative incidence to be 4.8 % (95 % confidence interval 3.2-7.3 %). The overall oral HPV clearance was reported to be 0-80 % between studies, and the median time to clearance from 6.5 to 18 months. Oral HPV-16 clearance was 43-83 %, and median time to clearance for HPV-16 was 7-22 months. Oral HPV prevalence, incidence and clearance vary considerably between published studies from different geographical regions. Further research is required to identify predictors of persistent oral HPV infection. Measurable baseline prevalence was observed in all studies, as well as non-trivial incidence of newly acquired oral HPV infections and incomplete clearance.

Pre-oncall key conditions training for first-year radiology registrars.

INTRODUCTION: The Royal Australian and New Zealand College of Radiology (RANZCR) recognised the importance of experience in on-call and emergency radiology for first-year registrars by introducing 'Key conditions in Year 1 training'. This list of common radiological pathologies can help to focus preparations for new registrars as they prepare for after-hours duties. METHODS: The Royal Brisbane and Women's Hospital (RBWH) implemented a 12-week formal training programme, based on this curriculum, for new registrars prior to commencing after-hours work. Its impact was assessed by an image recognition and interpretation examination that was administered to registrars before and after training. RESULTS: Examination results revealed that the prescribed training programme significantly increased both the rate and accuracy of reporting, and that improvements in speed were not at the expense of accuracy. Furthermore, it showed that a 12-week training programme was able to improve novice radiology registrars' ability to detect radiological abnormalities above that of experienced emergency department clinicians. Performances of consultant radiologists were used as a 'gold standard' control. CONCLUSION: This research demonstrates the value of a formal training programme in preparing registrars for extended after-hours reporting duties and contributing to important departmental service provision.

Association between renal function and chemotherapy-related toxicity in older adults with cancer.

PURPOSE: To evaluate the association between renal function (RF) and chemotherapy-related toxicity (CRT) in older adults with cancer and to compare the effect of different RF formulas and body weight measurements on this association. METHODS: This is a secondary analysis of data from a prospective multicenter study of patients ≥ age 65 who were starting a new chemotherapy regimen. RF was estimated with 4 formulas (modified Jelliffe [Jelliffe], Cockcroft-Gault [CG], Wright, and Modification of Diet in Renal Disease [MDRD]), using actual, ideal and adjusted body weights for 492 patients. The association between baseline RF and grade 3-5 CRT was evaluated by unconditional logistic regression. RESULTS: As a continuous variable, decreased creatinine clearance (CrCl) calculated by CG with actual body weight was associated with increased odds of CRT (OR 1.12, P<0.01; 95% CI 1.04-1.20) indicating that on average for every 10mL/min decrease in CrCl the odds of CRT increased by 12%. Very low RF (in the lowest 10%) with all formulas (CG, Jelliffe, Wright and MDRD) was associated with increased odds for CRT. This association is independent of the type of chemotherapy received (those requiring dose adjustment for renal function vs not). Neither primary dose reduction nor chemotherapy duration was associated with CRT. Serum creatinine alone was not associated with increased odds of CRT (OR 0.67, P=0.15). CONCLUSIONS: Decreased RF is associated with increased odds of CRT and should be considered when assessing risk of CRT in older adults with cancer. Serum creatinine alone is not adequate for risk assessment.

Prospective study of definitive chemoradiation in locally or regionally advanced squamous cell carcinoma of the skin.

BACKGROUND: The purpose of this study was to present our evaluation of the outcomes of concurrent chemoradiotherapy (CRT) in patients with locally advanced cutaneous squamous cell carcinoma (SCC). METHODS: This was a prospective phase II study. The primary endpoint was complete response (CR). Patients with locally/regionally advanced cutaneous SCC deemed unsuitable for surgery received definitive radiotherapy (RT; 70 Gy in 35fractions) and concurrent weekly platinum-based chemotherapy (cisplatin 40 mg/m2 or carboplatin area under the curve 2). RESULTS: Twenty-one patients were enrolled in this study. Eighteen patients had a locally advanced primary or nodal disease in the head and neck region with 66% having stage IV nonmetastatic disease. Of 19 evaluable patients, 10 achieved a CR to definitive CRT with 2 further patients rendered disease-free by salvage surgery for an overall CR of 63%. CONCLUSION: This is the only prospective series of CRT for cutaneous SCC. A high CR rate was documented in patients with locoregional advanced disease who were unable to undergo surgery. © 2016 Wiley Periodicals, Inc. Head Neck 39: 679-683, 2017.

Effect of increasing radiation dose on pathologic complete response in rectal cancer patients treated with neoadjuvant chemoradiation therapy.

BACKGROUND: Neoadjuvant chemoradiation therapy (CRT) increases pathological complete response (pCR) rates compared to radiotherapy alone in patients with stage II-III rectal cancer. Limited evidence addresses whether radiotherapy dose escalation further improves pCR rates. Our purpose is to measure the effects of radiotherapy dose and other factors on post-therapy pathologic tumor (ypT) and nodal stage in rectal cancer patients treated with neoadjuvant CRT followed by mesorectal excision. MATERIAL AND METHODS: A non-randomized comparative effectiveness analysis was performed of rectal cancer patients treated in 2000-2013 from the National Oncology Data Alliance™ (NODA), a pooled database of cancer registries from >150 US hospitals. The NODA contains the same data submitted to state cancer registries and SEER combined with validated radiotherapy and chemotherapy records. Eligible patients were treated with neoadjuvant CRT followed by proctectomy and had complete data on treatment start dates, radiotherapy dose, clinical tumor (cT) and ypT stage, and number of positive nodes at surgery (n = 3298 patients). Multivariable logistic regression was used to assess the predictive value of independent variables on achieving a pCR. RESULTS: On multivariable regression, radiotherapy dose, cT stage, and time interval between CRT and surgery were significant predictors of achieving a pCR. After adjusting for the effect of other variates, patients treated with higher radiotherapy doses were also more likely to have negative nodes at surgery and be downstaged from cT3-T4 and/or node positive disease to ypT0-T2N0 after neoadjuvant CRT. CONCLUSION: Our study suggests that increasing dose significantly improved pCR rates and downstaging in rectal cancer patients treated with neoadjuvant CRT followed by surgery.

Presurgical Biomarker Performance in the Detection of Gleason Upgrading in Prostate Cancer.

BACKGROUND: Gleason Score (GS) upgrading is generally considered a trigger for exit to definitive treatment during active surveillance (AS). Predicting the potential for GS upgrading would be of value in assessing AS eligibility. METHODS: We assessed the performance of biomarkers in presurgical specimens of expressed prostatic secretion (EPS) in this setting. RESULTS: Although EPS volume, total recovered RNA, and RNA expression biomarkers (TMPRSS2: ERG, PCA3, PSA) have been successful in both biopsy outcome prediction, and in the prediction of upstaging in active surveillance eligible patients, they were unable to predict upgrading in patients eligible for active surveillance under National Comprehensive Cancer Network guidelines. CONCLUSIONS: These biomarkers do not improve the prediction of upgrading over indications from standard clinical parameters. IMPACT: Additional biomarkers will be needed in this area. Cancer Epidemiol Biomarkers Prev; 25(12); 1643-5. ©2016 AACR.

Proteoform-Specific Insights into Cellular Proteome Regulation.

Knowledge regarding compositions of proteomes at the proteoform level enhances insights into cellular phenotypes. A strategy is described herein for discovery of proteoform-specific information about cellular proteomes. This strategy involved analysis of data obtained by bottom-up mass spectrometry of multiple protein OGE separations on a fraction by fraction basis. The strategy was exemplified using five matched sets of lysates of uninfected and human respiratory syncytial virus-infected A549 cells. Template matching demonstrated that 67.3% of 10475 protein profiles identified focused to narrow pI windows indicative of efficacious focusing. Furthermore, correlation between experimental and theoretical pI gradients indicated reproducible focusing. Based on these observations a proteoform profiling strategy was developed to identify proteoforms, detect proteoform diversity and discover potential proteoform regulation. One component of this strategy involved examination of the focusing profiles for protein groups. A novel concordance analysis facilitated differentiation between proteoforms, including proteoforms generated by alternate splicing and proteolysis. Evaluation of focusing profiles and concordance analysis were applicable to cells from a single and/or multiple biological states. Statistical analyses identified proteoform variation between biological states. Regulation relevant to cellular responses to human respiratory syncytial virus was revealed. Western blotting and Protomap analyses validated the proteoform regulation. Discovery of STAT1, WARS, MX1, and HSPB1 proteoform regulation by human respiratory syncytial virus highlighted the impact of the profiling strategy. Novel truncated proteoforms of MX1 were identified in infected cells and phosphorylation driven regulation of HSPB1 proteoforms was correlated with infection. The proteoform profiling strategy is generally applicable to investigating interactions between viruses and host cells and the analysis of other biological systems.