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Background: Few studies have assessed interventions aimed at managing nonmedical opioid use (NMOU) behavior among patients with cancer. The authors developed the Compassionate High-Alert Team (CHAT) intervention to manage patients receiving opioids for cancer pain who demonstrate NMOU behavior. The objective of this study was to determine the change in frequency of NMOU behaviors, pain intensity, and opioid requirements among those who received the intervention., Methods: A total of 130 patients receiving opioids for cancer pain that had documented evidence of NMOU and received the CHAT intervention were reviewed. Demographic and clinical information such as NMOU behaviors, pain scores, and morphine equivalent daily dose at baseline, 3, and 6 months post-intervention was obtained., Results: NMOU behaviors significantly decreased from a median (interquartile range) of 2 (1-3) at baseline to 0 (0-1) at both 3 and 6 months post-intervention (p < .001). A total of 45 of 75 (60%) and 31 of 50 (62%) of CHAT recipients achieved complete response to the intervention at 3 and 6 months, respectively. Higher baseline number of NMOU behaviors was independently associated with patient response to the intervention (odds ratio [OR], 1.97; 95% confidence interval [CI],1.09-4.28, p = .049 at 3 months; OR, 2.5; 95% CI, 1.20-6.47, p = .03 at 6 months). The median pain score decreased from 7 at baseline to 6 at both 3 and 6 months (p = .01). Morphine equivalent daily dose did not significantly change during that same period (143 mg/day vs. 139 mg/day, p = .13)., Conclusions: Most patients who received the CHAT intervention improved in their NMOU behaviors and pain intensity scores 3 and 6 months post-intervention. These preliminary findings support the efficacy of CHAT in managing patients receiving opioids for cancer pain who demonstrate NMOU behavior., (© 2022 American Cancer Society.)

Background: Telemedicine use has increased significantly during the COVID-19 pandemic. It remains unclear if its rapid growth exacerbates disparities in healthcare access. We aimed to characterize telemedicine use among a large oncology population in the Deep South during the COVID-19 pandemic., Materials and Methods: A retrospective cohort study was performed at the only National Cancer Institute designated-cancer center in Alabama March 2020 to December 2020. With a diverse (26.5% Black, 61% rural) population, this southeastern demographic uniquely reflects historically vulnerable populations. All non-procedural visits at the cancer center from March to December 2020 were included in this study excluding those with a department that had fewer than 100 visits during this time period. Patient and clinic level characteristics were analyzed using t-test and Chi-square to compare characteristics between visit types (in-person versus telemedicine, and video versus audio within telemedicine). Generalized estimating equations were used to identify independent factors associated with telemedicine use and type of telemedicine use., Results: There were 50 519 visits and most were in-person (81.3%). Among telemedicine visits, most were phone based (58.3%). Black race and male sex predicted in-person visits. Telemedicine visits were less likely to have video among patients who were Black, older, male, publicly insured, and from lower income areas., Conclusions: Telemedicine use, specifically with video, is significantly lower among historically vulnerable populations. Understanding barriers to telemedicine use and preferred modalities of communication among different populations will help inform insurance reimbursement and interventions at different socioecological levels to ensure the continued evolution of telemedicine is equitable., (© The Author(s) 2022. Published by Oxford University Press.)

Dietary patterns contribute to cancer risk. Separately, microbial factors influence the development of several cancers. However, the interaction of diet and the microbiome and their joint contribution to cancer treatment response needs more research. The microbiome significantly impacts drug metabolism, immune activation, and response to immunotherapy. One of the critical factors affecting the microbiome structure and function is diet. Data demonstrate that the diet and microbiome composition affects the immune response. Moreover, malnutrition is a significant confounder to cancer therapy response. There is little understanding of the interaction of malnutrition with the microbiome in the context of cancer. This review aims to address the current knowledge of dietary intake patterns and malnutrition among cancer patients and the impact on treatment outcomes. Second, this review will provide evidence linking the microbiome to cancer treatment response and provide evidence of the potentially strong effect that diet could have on this interaction. This review will formulate critical questions that will need further research to understand the diet-microbiome relationship in cancer treatment response and directions for future research to guide us to precision nutrition therapy to improve cancer outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visit NCCN.org.

Introduction: As healthcare systems are adapting due to COVID-19, there has been an increased need for telehealth in the outpatient setting. Not all patients have been comfortable with this transition. We sought to determine the relationship between health literacy and technological comfort in our cancer patients., Methods: We conducted a survey of patients that presented to the oncology clinics at a single-center over a 2-month period. Patients were given a voluntary, anonymous, survey during their visit containing questions regarding demographics, health literacy and technological comfort., Results: 344 surveys were returned (response-rate 64.3%). The median patient age was 61 years, 70% of responders were female and the most common race was White (67.3%). Increasing patient age, male gender, Black and Native-American race, decreased health literacy and lack of home broadband were associated with lower technological comfort score., Conclusion: In our cohort, patients with lower health literacy scores, older and male patients, or who have poor internet access showed a lower level of technological comfort. At risk patients can be identified and provided additional support in their use of telehealth services., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) and genomic biomarker-driven targeted therapies have revolutionized the modern oncologic treatment arsenal. The next step has been to combine targeted agents and ICIs. In doing so, some combination regimens may be more logical than others., Patients and Methods: Whole-exome and whole-transcriptome sequencing were performed on 2739 unselected later-stage clinical cases from 24 solid tumor subtypes in the NantHealth database, and data were also curated from 5746 similarly sequenced patients across 28 solid tumor subtypes in The Cancer Genome Atlas (TCGA). Significant differential expression of 10 immunoregulatory molecules [IRMs (genes)] was analyzed for association with mutant versus wild-type genes., Results: Twenty-three significant associations between currently actionable variants and RNA-expressed checkpoint genes were identified in the TCGA cases; 10 were validated in the external cohort of 2739 clinical cases from NantHealth (P values were adjusted using Benjamini-Hochberg multiple hypothesis correction to reduce false-discovery rate). Within the same 5746 TCGA profiles, 2740 TCGA patients were identified as having one or more potentially oncogenic single-nucleotide variant (SNV) mutation within an established 50-gene hotspot panel. Of the 50 genes, SNVs within 15 were found to be significantly associated with differential expression of at least one IRM after adjusting for tissue enrichment; six were confirmed significant associations in an independent set of 2739 clinical cases from NantHealth., Conclusions: Logically combining ICIs with targeted therapies may offer unique treatment strategies for patients with cancer. The presence of specific mutations impacts the expression of IRMs, an observation of potential importance for selecting combinations of gene- and immune-targeted therapeutics., Competing Interests: Disclosure JJA and AG have no disclosures. CWS, SV, AP, and SKR are employees of NantHealth. SK consults for Foundation Medicine; reports speaker’s fee from Roche, and research grant from ACT Genomics, Sysmex, Konica Minolta, and OmniSeq. RK has research funding from Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, Boehringer Ingelheim, and Konica Minolta, as well as receiving consultant and/or speaker fees from LOXO, X-Biotech, Actuate Therapeutics, Genentech, Pfizer, Roche, and NeoMed. RK has an equity interest in IDbyDNA and CureMatch, Inc and is a board member of CureMatch and CureMetrix and a co-founder of CureMatch., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Receptor clustering is the first and critical step to activate apoptosis by death receptor-5 (DR5). The recent discovery of the autoinhibitory DR5 ectodomain has challenged the long-standing view of its mechanistic activation by the natural ligand Apo2L. Because the autoinhibitory residues have remained unknown, here we characterize a crucial patch of positively charged residues (PPCR) in the highly variable domain of DR5. The PPCR electrostatically separates DR5 receptors to autoinhibit their clustering in the absence of ligand and antibody binding. Mutational substitution and antibody-mediated PPCR interference resulted in increased apoptotic cytotoxic function. A dually specific antibody that enables sustained tampering with PPCR function exceptionally enhanced DR5 clustering and apoptotic activation and distinctively improved the survival of animals bearing aggressive metastatic and recurrent tumors, whereas clinically tested DR5 antibodies without PPCR blockade function were largely ineffective. Our study provides mechanistic insights into DR5 activation and a therapeutic analytical design for potential clinical success., Competing Interests: Declaration of interests Some components of PPCR discovery and 2DEI design are part of a pending provisional patent by J.T.-S. on behalf of the University of Virginia License and Venture Group., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Inhibition of the extracellular signal-regulated kinases ERK1 and ERK2 (ERK1/2) offers a promising therapeutic strategy in cancers harboring activated RAS/RAF/MEK/ERK signaling pathways. Here, we describe an orally bioavailable and selective ERK1/2 inhibitor, ASN007, currently in clinical development for the treatment of cancer. In preclinical studies, ASN007 shows strong antiproliferative activity in tumors harboring mutations in BRAF and RAS (KRAS, NRAS, and HRAS). ASN007 demonstrates activity in a BRAF V600E mutant melanoma tumor model that is resistant to BRAF and MEK inhibitors. The PI3K inhibitor copanlisib enhances the antiproliferative activity of ASN007 both in vitro and in vivo due to dual inhibition of RAS/MAPK and PI3K survival pathways. Our data provide a rationale for evaluating ASN007 in RAS/RAF-driven tumors as well as a mechanistic basis for combining ASN007 with PI3K inhibitors., Competing Interests: A.Y. has received honoraria and/or consultancy fees from Abbvie, Biopath, Curis, Epizyme, Janssen, Merck, Roche, Takeda, and Xynomic and has received research support from Janssen, Curis, Merck, BMS, Syndax, and Roche. S.T., S.G., and L.D. are employees and shareholders of Asana BioSciences. R.A.S. is a shareholder in and consultant to Asana BioSciences. S.T., R.A.S., and S.R. are inventors on three patents covering ASN007 and related compounds and their use in the treatment of cancer. The other authors declare no competing interests., (© 2021.)

Importance: One of the main aims of research on nonmedical opioid use (NMOU) is to reduce the frequency of NMOU behaviors through interventions such as universal screening, reduced opioid exposure, and more intense follow-up of patients with elevated risk. The absence of data on the frequency of NMOU behavior is the major barrier to conducting research on NMOU., Objective: To determine the overall frequency of and the independent predictors for NMOU behavior., Design, Setting, and Participants: In this prognostic study, 3615 patients with cancer were referred to the supportive care center at MD Anderson Cancer Center from March 18, 2016, to June 6, 2018. Patients were eligible for inclusion if they had cancer and were taking opioids for cancer pain for at least 1 week. Patients were excluded if they had no follow-up within 3 months of initial consultation, did not complete the appropriate questionnaire, or did not have scheduled opioid treatments. After exclusion, a total of 1554 consecutive patients were assessed for NMOU behavior using established diagnostic criteria. All patients were assessed using the Edmonton Symptom Assessment Scale, the Screener and Opioid Assessment for Patients with Pain (SOAPP), and the Cut Down, Annoyed, Guilty, Eye Opener-Adapted to Include Drugs (CAGE-AID) survey. Data were analyzed from January 6 to September 25, 2020., Results: A total of 1554 patients (median [interquartile range (IQR)] age, 61 [IQR, 52-69] years; 816 women [52.5%]; 1124 White patients [72.3%]) were evaluable for the study, and 299 patients (19.2%) had 1 or more NMOU behaviors. The median (IQR) number of NMOU behaviors per patient was 1 (IQR, 1-3). A total of 576 of 745 NMOU behaviors (77%) occurred by the first 2 follow-up visits. The most frequent NMOU behavior was unscheduled clinic visits for inappropriate refills (218 of 745 [29%]). Eighty-eight of 299 patients (29.4%) scored 7 or higher on SOAPP, and 48 (16.6%) scored at least 2 out of 4 points on the CAGE-AID survey. Results from the multivariate model suggest that marital status (single, hazard ratio [HR], 1.58; 95% CI, 1.15-2.18; P = .005; divorced, HR, 1.43; 95% CI, 1.01-2.03; P = .04), SOAPP score (positive vs negative, HR, 1.35; 95% CI, 1.04-1.74; P = .02), morphine equivalent daily dose (MEDD) (HR, 1.003; 95% CI, 1.002-1.004; P < .001), and Edmonton Symptom Assessment Scale pain level (HR, 1.11; 95% CI, 1.06-1.16; P < .001) were independently associated with the presence of NMOU behavior. In recursive partition analysis, single marital status, MEDD greater than 50 mg, and SOAPP scores greater than 7 were associated with a higher risk (56%) for the presence of NMOU behavior., Conclusions and Relevance: This prognostic study of patients with cancer taking opioids for cancer pain found that 19% of patients developed NMOU behavior within a median duration of 8 weeks after initial supportive care clinic consultation. Marital status (single or divorced), SOAPP score greater than 7, higher levels of pain severity, and MEDD level were independently associated with NMOU behavior. This information will assist clinicians and investigators designing clinical and research programs in this important field.

Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies., Competing Interests: The authors declare no competing interest.

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor-related diarrhea/colitis and cardiovascular irAEs.

Background: The FDA initially approved pembrolizumab and nivolumab for doses based on patient weight, but subsequently amended approval to fixed doses. We estimated savings from novel dosing strategies based on real-world patient data from a single cancer center., Methods: We analyzed all outpatient doses of pembrolizumab and nivolumab administered at three infusion centers affiliated with our academic hospital between July 1, 2018 and Oct 31, 2018. We estimated savings from several dosing strategies with and without vial sharing between patients., Results: A total of 1029 doses of pembrolizumab or nivolumab were administered for multiple cancer types. For 77% of doses, the weight-based dose was less than the fixed dose. "Dose-minimization" (DM), defined as the lesser of weight-based and fixed dose decreased nivolumab spending by 9% without affecting pembrolizumab spending. DM plus vial sharing decreased pembrolizumab spending by 19% without affecting nivolumab. The differences in savings were due to availability of multiple vial sizes for nivolumab but not pembrolizumab. DM plus vial sharing for both drugs would have saved $1.5 million USD over the 4-month study period., Conclusion: New dosing strategies for pembrolizumab and nivolumab can generate large savings without anticipated decrease in efficacy. Barriers include FDA dosing labels, hospital policies against vial sharing, and inaccessibility of smaller vial sizes, which are currently available in other worldwide markets., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Context: The optimal dose of fentanyl sublingual spray (FSS) for exertional dyspnea has not been determined., Objectives: We examined the effect of two doses of prophylactic FSS on exertional dyspnea., Methods: In this parallel, dose-finding, double-blind randomized clinical trial, opioid-tolerant cancer patients completed a shuttle walk test at baseline. Patients completed a second shuttle walk test 10 minutes after a single dose of FSS equivalent to either 35%-45% (high dose) or 15%-25% (low dose) of the total daily opioid dose. The primary outcome was change in modified dyspnea Borg scale (0-10) between the first and second shuttle walk tests. Secondary outcomes included adverse events as well as changes in walk distance, vital signs, and neurocognitive function., Results: Thirty of the 50 enrolled patients completed the study. High-dose FSS (n = 13) resulted in significantly lower dyspnea (mean change -1.42; 95% CI -2.37, -0.48; P = 0.007) and greater walk distance (mean change 44 m; P = 0.001) compared to baseline. Low-dose FSS (n = 17) resulted in a nonsignificant reduction in dyspnea (mean change -0.47; 95% CI -1.26, 0.32; P = 0.24) and significant increase in walk distance (mean change 24 m; P = 0.01) compared to baseline. Global evaluation showed high-dose group was more likely to report at least somewhat better improvement (64% vs. 24%; P = 0.06). No significant adverse events or detriment to vital signs or neurocognitive function was detected., Conclusion: Prophylactic FSS was well tolerated and demonstrated a dose-response relationship in improving both dyspnea and walk distance. High-dose FSS should be tested in confirmatory trials., (Copyright © 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visit NCCN.org.

Background: The Richmond Agitation-Sedation Scale (RASS) is commonly used to assess psychomotor activity; however, to the authors' knowledge, its minimal clinically important difference (MCID) has not been determined to date. The objective of the current study was to identify the MCID for RASS using 2 anchor-based approaches., Methods: The current study was a secondary analysis of a randomized controlled trial to compare the effect of lorazepam versus placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium. The primary outcome was change in RASS (10-point numeric rating scale ranging from -5 [unarousable] to +4 [combative]) from baseline to 8 hours after treatment administration. The sensitivity-specificity and within-patient change methods were used to identify the MCID, with the anchor being patient comfort after the study intervention as perceived by caregivers and nurses., Results: A total of 90 patients were randomized and 58 (64%) received the study medication for restlessness/agitation (mean baseline RASS, 1.6). A total of 23 caregivers (61%) and 23 nurses (55%) perceived that the patient was more comfortable after treatment. Using the sensitivity-specificity method, the optimal RASS reduction was ≥4 points according to both caregivers (sensitivity of 61% and specificity of 80%; area under the curve, 0.71) and nurses (sensitivity of 73% and specificity of 84%; area under the curve, 0.78). The RASS cutoff value based on the within-patient change method was similar (-4.2 for caregivers and -4.0 for nurses)., Conclusions: For patients with persistent restlessness/agitation, a reduction of ≥4 points in RASS was considered to be the MCID for both nurses and caregivers. These preliminary findings may have implications for sample size calculation and the interpretation of treatment effect in future delirium trials. Cancer 2018;124:2246-52. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Background: Data on the development and outcomes of effective interventions to address aberrant opioid-related behavior (AB) in patients with cancer are lacking. Our outpatient supportive care clinic developed and implemented a specialized interdisciplinary team approach to manage patients with AB. The purpose of this study was to report clinical outcomes of this novel intervention., Materials and Methods: The medical records of 30 consecutive patients with evidence of AB who received the intervention and a random control group of 70 patients without evidence of AB between January 1, 2015, and August 31, 2016, were reviewed., Results: At baseline, pain intensity ( p  = .002) and opioid dose ( p  = .001) were significantly higher among patients with AB. During the course of the study, the median number of ABs per month significantly decreased from three preintervention to 0.4 postintervention ( p  < .0001). The median morphine equivalent daily dose decreased from 165 mg/day at the first intervention visit to 112 mg/day at the last follow-up ( p  = .018), although pain intensity did not significantly change ( p  = .984). "Request for opioid medication refills in the clinic earlier than the expected time" was the AB with the highest frequency prior to the intervention and the greatest improvement during the study period. Younger age ( p  < .0001) and higher Edmonton Symptom Assessment System anxiety score ( p  = .005) were independent predictors of the presence of AB., Conclusion: The intervention was associated with a reduction in the frequency of AB and opioid utilization among patients with cancer receiving chronic opioid therapy. More research is needed to further characterize the clinical effectiveness of this intervention., Implications for Practice: There are currently no well-defined and evidence-based strategies to manage cancer patients on chronic opioid therapy who demonstrate aberrant opioid-related behavior. The findings of this study offer a promising starting point for the creation of a standardized strategy for clinicians and provides valuable information to guide their practice regarding these patients. The study results will also help clinicians to better understand the types and frequencies of the most common aberrant behaviors observed among patients with cancer who are receiving chronic opioid therapy. This will enhance the process of timely patient identification, management, or referral to the appropriate specialist teams., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2017.)

Purpose: To investigate the utilization of palliative radiation therapy (RT), predictors for the use of RT, and symptom palliation following RT during the last 30 days of life through systemic review of literature., Materials/methods: A systematic search of available medical literature databases was performed on patients receiving palliative RT in the last 30 days of life. A total of 18 studies were evaluated., Results: The overall palliative RT utilization rates during the last month of life were in the range of 5-10% among patients who died of cancer and 9-15.3% of patients who received palliative RT. The most commonly used regimen was 30 Gy in 10 fractions (36-90%). Single fraction RT utilization ranged from 0% to 59%. ECOG performance status 3-4 was significantly associated with patients receiving RT in the last 30 days of life and shorter survival. Twenty-six percent of patients who survived less than 1 month were reported to show symptom palliation following RT., Conclusion: Palliative RT was performed in approximately 10% of patients who died of cancer near their end of life, with the most commonly used regimen of 30 Gy in 10 fractions. This study suggests that greater use of shorter or single fraction regimens may be beneficial, especially in patients with poor performance status., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: CXCL12 (SDF1) is reported to promote cancer progression in several preclinical models and this is corroborated by the analysis of human tissue specimens. However, the relationship between CXCL12 expression and cancer survival has not been systematically assessed., Methods: We conducted a systematic review and meta-analysis of studies that evaluated the association between CXCL12 expression and cancer survival., Results: Thirty-eight studies inclusive of 5807 patients were included in the analysis of overall, recurrence-free or cancer-specific survival, the majority of which were retrospective. The pooled hazard ratios (HRs) for overall and recurrence-free survival in patients with high CXCL12 expression were 1.39 (95% CI: 1.17-1.65, P=0.0002) and 1.12 (95% CI: 0.82-1.53, P=0.48) respectively, but with significant heterogeneity between studies. On subgroup analysis by cancer type, high CXCL12 expression was associated with reduced overall survival in patients with oesophagogastric (HR 2.08; 95% CI: 1.31-3.33, P=0.002), pancreatic (HR 1.54; 95% CI: 1.21-1.97, P=0.0005) and lung cancer (HR 1.37; 95% CI: 1.08-1.75, P=0.01), whereas in breast cancer patients high CXCL12 expression conferred an overall survival advantage (HR 0.5; 95% CI: 0.38-0.66, P<0.00001)., Conclusions: Determination of CXCL12 expression has the potential to be of use as a cancer biomarker and adds prognostic information in various cancer types. Prospective or prospective-retrospective analyses of CXCL12 expression in clearly defined cancer cohorts are now required to advance our understanding of the relationship between CXCL12 expression and cancer outcome.

Background: Patients with advanced cancer who progress on standard therapy are potential candidates for phase I clinical trials. Due to their aggressive disease and complex comorbid conditions, these patients often need inpatient admission. This study assessed the outcomes of such patients after they were discharged to hospice care., Patients and Methods: We performed a retrospective analysis of patients with solid tumor malignancies who were discharged to hospice care from the inpatient service., Results: One hundred thirty-three patients were included in the study cohort. All patients had metastatic disease and an Eastern Cooperative Oncology Group performance status ≥3. The median survival after discharge to hospice from an inpatient setting was 16 days, with a survival rate of 5% at 3 months after discharge. The median survival after the last cancer treatment was 46 days, with survival of 17% at 3 months, and 5% at 6 months. Patients with lactate dehydrogenase (LDH) >618 IU/L had a median post-discharge survival of 11 days versus 20 days for patients with LDH ≤618 IU/L., Conclusions: Patients with metastatic cancer participating in phase I trials who have poor performance status and require inpatient admission have a very short survival after discharge to hospice. A high LDH level predicts an even shorter survival., Competing Interests: of potential conflicts of interests: No potential conflicts of interest were disclosed by the authors., (© 2016 S. Karger AG, Basel.)

Background: Data are limited on the use and outcomes of urine drug tests (UDTs) among patients with advanced cancer. The main objective of this study was to determine the factors associated with UDT ordering and results in outpatients with advanced cancer., Methods: A retrospective chart review was conducted of 1058 patients who attended an outpatient supportive care clinic from March 2014 to November 2015. Sixty-one patients who were receiving chronic opioid therapy and underwent UDTs were identified. A control group of 120 patients who did not undergo UDTs was selected for comparison., Results: Sixty-one of 1058 patients (6%) underwent UDTs, and 33 of 61 patients (54%) had abnormal results. Multivariate analysis indicated that the odds ratio for UDT ordering was 3.9 in patients who had positive Cut Down, Annoyed, Guilty, and Eye Opener (CAGE) questionnaire results (P = .002), 4.41 in patients aged < 45 years (P < .001), 5.58 in patients who had moderate-to-severe pain (Edmonton Symptom Assessment Scale pain scores ≥4; P < .001), 0.27 in patients with advanced-stage cancer, (P = .008), and 0.25 in patients who had moderate-to-severe fatigue (P = .001). Among 52 abnormal UDT results in 33 patients, the most common opioid findings were prescribed opioids absent in urine (14 of 52 tests; 27%) and unprescribed opioids in urine (13 of 52 tests; 25%)., Conclusions: UDTs were used infrequently among outpatients with advanced cancer who were receiving chronic opioid therapy. Younger age, positive CAGE questionnaire results, early stage cancer or no evidence of disease status, higher pain intensity, and lower fatigue scores were significant predictors of UDT ordering. More than 50% of UDT results were abnormal. More research is necessary to better characterize aberrant opioid use in patients with advanced cancer. Cancer 2016;122:3732-9. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Importance: Molecular aberrations in the phosphatidylinositol-3-kinase (PI3K) pathway drive tumorigenesis. Frequently co-occurring alterations in hormone receptors and/or human epidermal growth factor receptor 2 (HER2) may be relevant to mechanisms of response and resistance., Objective: To identify patterns of aberration in the PI3K and interactive pathways that might lead to targeted therapy opportunities in clinical practice., Design, Setting, and Participants: From January 2013 through December 2014, 19 784 consecutive tumor samples (>40 cancer types) were sent from thousands of clinicians in 60 countries to a single commercial laboratory for molecular profiling, including next generation sequencing, protein expression (immunohistochemical analysis [IHC]), and gene amplification (fluorescent in situ hybridization or chromogenic in situ hybridization)., Main Outcomes and Measures: Patterns in targetable genomic and proteomic alterations in the PI3K pathway and coincidence with hormone receptor and HER2 alterations., Exposures: Molecular profiling across solid tumors., Results: Overall, 38% of patients had an alteration in 1 or more PI3K pathway components, most commonly phosphatase and tensin homologue (PTEN) loss (by IHC) (30% of all patients), followed by mutations in PIK3CA (13%), PTEN (6%), or AKT1 (1%). Seventy percent of patients with endometrial cancer and more than 50% of patients with breast, prostate, anal, hepatocellular, colorectal, and cervical cancer exhibited alterations in at least 1 PI3K pathway gene and/or gene product. Examples of frequent aberrations included PTEN loss in hepatocellular (57% of patients), colorectal (48%), gastric (36%), prostate (52%), and endometrial cancer (49%); PIK3CA mutations in endometrial (37%), breast (31%), cervical (29%), and anal cancer (27%). PIK3CA, PTEN, and AKT1 mutations occurred more frequently in the presence of hormone receptor overexpression (androgen, progesterone, or estrogen receptor). PIK3CA mutations were also more common in the HER2-positive than in the HER2-negative group; the opposite pattern was seen for PTEN mutation or PTEN loss., Conclusions and Relevance: PI3K pathway aberrations are among the most common in cancer. They do not segregate by classic cancer histologic characteristics. Patterns of biomarker coalterations involving HER2 and hormone receptors may be important for optimizing combination treatments across cancer types.

Background: Although various studies revealed the beneficial effects of statins in post-cardiac transplant patients, these were relatively small and low-powered studies. We performed a meta-analysis of published studies to evaluate the role of statins in post-cardiac transplant patients, specifically examining the effects on hemodynamically significant/fatal graft rejection, coronary vasculopathy, terminal cancer, and overall survival., Methods and Results: We searched PubMed, Cochran CENTRAL, and Web of Science databases using the search terms "cardiac transplant" or "heart transplant," and "statin" for a literature search. A random-effects model with Mantel-Haenszel method was used to pool the data. We identified 10 studies, 4 randomized controlled trials, and 6 nonrandomized studies, which compared outcomes in heart transplant recipients undergoing statin therapy to statin-naive patients. A pooled analysis of 9 studies reporting mortality revealed that the use of statins was associated with significant reduction in all-cause mortality (odds ratio, 0.26; 95% confidence interval, 0.20-0.35; P<0.0001). Statins also decreased the odds of hemodynamically significant/fatal rejection (odds ratio, 0.37; 95% confidence interval, 0.21-0.65; P=0.0005), incidence of coronary vasculopathy (odds ratio, 0.33; 95% confidence interval, 0.16-0.68; P=0.003), and terminal cancer (odds ratio, 0.30; 95% confidence interval, 0.15-0.63; P=0.002)., Conclusions: The evidence from a pooled analysis suggests that statins improve survival in heart transplant recipients. Statins may prevent fatal rejection episodes, decrease terminal cancer risk, and reduce the incidence of coronary vasculopathy. Additional prospective studies are needed to further investigate and explain this association., (© 2016 American Heart Association, Inc.)

Objectives: To describe cancer inpatients' prior-year use of complementary and integrative health (CIH) therapies and interest in receiving CIH therapies while in the hospital., Design: Observational, cross-sectional survey of prior-year use of 12 different CIH approaches and interest in receiving any of 7 CIH services in the hospital., Setting: Surgical oncology ward of an academic medical center., Participants: 166 hospitalized oncology patients, with an average age of 54 years., Results: The most commonly used CIH approach was vitamins/nutritional supplements (67%), followed by use of a special diet (42%) and manual therapies (39%). More than 40% of patients expressed interest in each of the therapies if it was offered during their hospital stay, and 95% of patients were interested in at least one. More than 75% expressed interest in nutritional counseling and in massage. CIH use and interest varied somewhat by demographic and clinical characteristics., Conclusion: Rates of CIH use among patients with cancer were high, as were their preferences to have these services available in the inpatient setting. Hospitals have the opportunity to provide patient-centered care by developing capacity to provide inpatient CIH services.

Background: Transdermal fentanyl (TDF) is 1 of the most common opioids prescribed to patients with cancer. However, the accurate opioid rotation ratio (ORR) from other opioids to TDF is unknown, and various currently used methods result in wide variation of the ORR. The objective of this study was to determine the ORR of the oral morphine equivalent daily dose (MEDD) to the TDF dose when correcting for the MEDD of breakthrough opioids (the net MEDD) in cancer outpatients., Methods: The records of 6790 consecutive patients were reviewed at the authors' supportive care center from 2010 to 2013 to identify those who underwent rotation from other opioids to TDF. Data regarding Edmonton Symptom Assessment Scale scores and MEDDs were collected for patients who returned for a follow-up visit within 5 weeks. Linear regression analysis was used to estimate the ORR between the TDF dose and the net MEDD (the MEDD before opioid rotation [OR] minus the MEDD of the breakthrough opioid used along with TDF after OR)., Results: In total, 129 patients underwent OR from other opioids to TDF. The mean patient age was 56 years, 59% were men, and 88% had advanced cancer. Uncontrolled pain (80%) was the most frequent reason for OR. In 101 patients who underwent OR and had no worsening of pain at follow-up, the median ORR from net MEDD to TDF (in mg per day) was 0.01 (range, -0.02 to 0.04), and the correlation coefficient of the TDF dose to the net MEDD was 0.77 (P < .0001). The ORR was not significantly impacted by body mass index or serum albumin. The ORR of 0.01 suggests that an MEDD of 100 mg is equivalent to 1 mg TDF daily or approximately 40 micrograms per hour of TDF (1000 micrograms/24 hours)., Conclusions: The median ORR from MEDD to TDF in mg per day was 0.01. These results warrant further studies., (© 2015 American Cancer Society.)

Background: Limited information is available on the symptomatic complications that occur in the last days of life., Aim: We documented the frequency, clinical course, and survival for 25 symptomatic complications among patients admitted to acute palliative care units., Design: Prospective longitudinal observational study., Measurements: Their attending physician completed a daily structured assessment of symptomatic complications from admission to discharge or death., Setting/participants: We enrolled consecutive advanced cancer patients admitted to acute palliative care units at MD Anderson Cancer Center, USA, and Barretos Cancer Hospital, Brazil., Results: A total of 352 patients were enrolled (MD Anderson Cancer Center = 151, Barretos Cancer Hospital = 201). Delirium, pneumonia, and bowel obstruction were the most common complications, occurring in 43%, 20%, and 16% of patients on admission, and 70%, 46%, and 35% during the entire acute palliative care unit stay, respectively. Symptomatic improvement for delirium (36/246, 15%), pneumonia (52/161, 32%), and bowel obstruction (41/124, 33%) was low. Survival analysis revealed that delirium (p < 0.001), pneumonia (p = 0.003), peritonitis (p = 0.03), metabolic acidosis (p < 0.001), and upper gastrointestinal bleed (p = 0.03) were associated with worse survival. Greater number of symptomatic complications on admission was also associated with poorer survival (p < 0.001)., Conclusion: Symptomatic complications were common in cancer patients admitted to acute palliative care units, often do not resolve completely, and were associated with a poor prognosis despite active medical management., (© The Author(s) 2015.)

Purpose: Cancer pain management guidelines recommend initial treatment with intermediate-strength analgesics such as hydrocodone and subsequent escalation to stronger opioids such as morphine. There are no published studies on the process of opioid rotation (OR) from hydrocodone to strong opioids in cancer patients. Our aim was to determine the opioid rotation ratio (ORR) of hydrocodone to morphine equivalent daily dose (MEDD) in cancer outpatients., Patients and Methods: We reviewed the records of consecutive patient visits at our supportive care center in 2011-2012 for OR from hydrocodone to stronger opioids. Data regarding demographics, Edmonton Symptom Assessment Scale (ESAS), and MEDD were collected from patients who returned for follow-up within 6 weeks. Linear regression analysis was used to estimate the ORR between hydrocodone and MEDD. Successful OR was defined as 2-point or 30% reduction in the pain score and continuation of the new opioid at follow-up., Results: Overall, 170 patients underwent OR from hydrocodone to stronger opioid. The median age was 59 years, and 81% had advanced cancer. The median time between OR and follow-up was 21 days. We found 53% had a successful OR with significant improvement in the ESAS pain and symptom distress scores. In 100 patients with complete OR and no worsening of pain at follow-up, the median ORR from hydrocodone to MEDD was 1.5 (quintiles 1-3: 0.9-2). The ORR was associated with hydrocodone dose (r = -.52; p < .0001) and was lower in patients receiving ≥40 mg of hydrocodone per day (p < .0001). The median ORR of hydrocodone to morphine was 1.5 (n = 44) and hydrocodone to oxycodone was 0.9 (n = 24)., Conclusion: The median ORR from hydrocodone to MEDD was 1.5 and varied according to hydrocodone dose., (©AlphaMed Press.)

Background: The physical signs of impending death have not been well characterized in cancer patients. A better understanding of these signs may improve the ability of clinicians to diagnose impending death. We examined the frequency and onset of 10 bedside physical signs and their diagnostic performance for impending death., Methods: We systematically documented 10 physical signs every 12 hours from admission to death or discharge in 357 consecutive patients with advanced cancer admitted to two acute palliative care units. We examined the frequency and median onset of each sign from death backward and calculated their likelihood ratios (LRs) associated with death within 3 days., Results: In total, 203 of 357 patients (52 of 151 in the U.S., 151 of 206 in Brazil) died. Decreased level of consciousness, Palliative Performance Scale ≤20%, and dysphagia of liquids appeared at high frequency and >3 days before death and had low specificity (<90%) and positive LR (<5) for impending death. In contrast, apnea periods, Cheyne-Stokes breathing, death rattle, peripheral cyanosis, pulselessness of radial artery, respiration with mandibular movement, and decreased urine output occurred mostly in the last 3 days of life and at lower frequency. Five of these signs had high specificity (>95%) and positive LRs for death within 3 days, including pulselessness of radial artery (positive LR: 15.6; 95% confidence interval [CI]: 13.7-17.4), respiration with mandibular movement (positive LR: 10; 95% CI: 9.1-10.9), decreased urine output (positive LR: 15.2; 95% CI: 13.4-17.1), Cheyne-Stokes breathing (positive LR: 12.4; 95% CI: 10.8-13.9), and death rattle (positive LR: 9; 95% CI: 8.1-9.8)., Conclusion: We identified highly specific physical signs associated with death within 3 days among cancer patients., (©AlphaMed Press.)

The Werner syndrome protein (WRN) is a nuclear protein required for cell growth and proliferation. Loss-of-function mutations in the Werner syndrome gene are associated with the premature onset of age-related diseases. How loss of WRN limits cell proliferation and induces replicative senescence is poorly understood. Here, we show that WRN depletion leads to a striking metabolic shift that coordinately weakens the pathways that generate reducing equivalents for detoxification of reactive oxygen species and increases mitochondrial respiration. In cancer cells, this metabolic shift counteracts the Warburg effect, a defining characteristic of many malignant cells, resulting in altered redox balance and accumulation of oxidative DNA damage that inhibits cell proliferation and induces a senescence-like phenotype. Consistent with these findings, supplementation with antioxidant rescues at least in part cell proliferation and decreases senescence in WRN-knockdown cancer cells. These results demonstrate that WRN plays a critical role in cancer cell proliferation by contributing to the Warburg effect and preventing metabolic stress.

Cancer, like any disease, is a pathologic biological process. Drugs are designed to interfere with the pathologic process and should therefore also be validated using a functional screening method directed at these processes. Screening for cancers at an appropriate time and also evaluating results is also very important. Volumetric measurement helps in better screening and evaluation of tumors. Volumetry is a process of quantification of the tumors by identification (pre-cancerous or target lesion) and measurement. Volumetric image analysis allows an accurate, precise, sensitive, and medically valuable assessment of tumor response. It also helps in identifying possible outcomes such disease progression (PD) or complete response as per Response Evaluation Criteria in Solid Tumors (RECIST).

To achieve malignancy, cancer cells convert numerous signaling pathways, with evasion from cell death being a characteristic hallmark. The cell death machinery represents an anti-cancer target demanding constant identification of tumor-specific signaling molecules. Control of mitochondrial radical formation, particularly superoxide interconnects cell death signals with appropriate mechanistic execution. Superoxide is potentially damaging, but also triggers mitochondrial cytochrome c release. While paraoxonase (PON) enzymes are known to protect against cardiovascular diseases, recent data revealed that PON2 attenuated mitochondrial radical formation and execution of cell death. Another family member, PON3, is poorly investigated. Using various cell culture systems and knockout mice, here we addressed its potential role in cancer. PON3 is found overexpressed in various human tumors and diminishes mitochondrial superoxide formation. It directly interacts with coenzyme Q10 and presumably acts by sequestering ubisemiquinone, leading to enhanced cell death resistance. Localized to the endoplasmic reticulum (ER) and mitochondria, PON3 abrogates apoptosis in response to DNA damage or intrinsic but not extrinsic stimulation. Moreover, PON3 impaired ER stress-induced apoptotic MAPK signaling and CHOP induction. Therefore, our study reveals the mechanism underlying PON3's anti-oxidative effect and demonstrates a previously unanticipated function in tumor cell development. We suggest PONs represent a novel class of enzymes crucially controlling mitochondrial radical generation and cell death.

At the end of life, patients often reflect on the meaning of their lives and decide how to best take advantage of the remaining time to accomplish their life goals. We report the case of a patient with advanced cancer who got married in our acute palliative care unit weeks before her death. Our interdisciplinary team was able to support her physically and emotionally, thereby assisting her in achieving her life goals. The wedding gave her the opportunity to acquire further meaning in life, deepen her connection with her loved ones, and enhance her sense of dignity, self-worth, and pride. It also was associated with a significant improvement in her symptoms and had a positive effect on the health care team. This example illustrates the effectiveness of a palliative care team in helping patients to achieve their life goals and supporting their families during a time when two major life events, marriage and end of life, occur concurrently., (Copyright © 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Clinicians have limited accuracy in the prediction of patient survival. We assessed the accuracy of probabilistic clinician prediction of survival (CPS) and temporal CPS for advanced cancer patients admitted to our acute palliative care unit, and identified factors associated with CPS accuracy. Eight physicians and 20 nurses provided their estimation of survival on admission by (a) the temporal approach, "What is the approximate survival for this patient (in days)?" and (b) the probabilistic approach, "What is the approximate probability that this patient will be alive (0%-100%)?" for ≥24 hours, 48 hours, 1 week, 2 weeks, 1 month, 3 months, and 6 months. We also collected patient and clinician demographics. Among 151 patients, the median age was 58 years, 95 (63%) were female, and 138 (81%) had solid tumors. The median overall survival time was 12 days. The median temporal CPS was 14 days for physicians and 20 days for nurses. Physicians were more accurate than nurses. A higher accuracy of temporal physician CPS was associated with older patient age. Probabilistic CPS was significantly more accurate than temporal CPS for both physicians and nurses, although this analysis was limited by the different criteria for determining accuracy. With the probabilistic approach, nurses were significantly more accurate at predicting survival at 24 hours and 48 hours, whereas physicians were significantly more accurate at predicting survival at 6 months. The probabilistic approach was associated with high accuracy and has practical implications.

Positron emission tomography (PET) is playing an increasingly important role in the diagnosis, staging, and monitoring response to treatment in a variety of cancers. Recent efforts have focused on immuno-PET, which uses antibody-based radiotracers, to image tumors based on expression of tumor-associated antigens. It is postulated that the specificity afforded by antibody targeting should both improve tumor detection and provide phenotypic information related to primary and metastatic lesions that will guide therapy decisions. Advances in antibody-engineering are providing the tools to develop antibody-based molecules with pharmacokinetic properties optimized for use as immuno-PET radiotracers. Coupled with technical advances in the design of PET scanners, immuno-PET holds promise to improve diagnostic imaging and to guide the use of targeted therapies. An overview of the preclinical immuno-PET studies in cancer models is reviewed here., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Recent reports suggest that high doses of methadone may prolong QTc interval and occasionally cause torsades de pointes; however, few of these studies involved the palliative care population., Objective: The purpose of this study was to determine the effect of initiation of methadone on QTc interval in patients with cancer pain seen at the palliative care setting., Methods: We enrolled 100 patients with cancer in this prospective study. Patients were followed clinically and electrocardiographically for QTc changes at baseline, 2, 4, and 8 weeks. Contributing factors for QTc prolongation such as medications, cardiovascular diseases, and electrolytes disturbances were documented. QTc prolongation was defined as greater than 430 ms in males and greater than 450 ms in females, and significant QTc prolongation was defined as QTc interval greater than 25% increase from baseline or 500 ms or more., Results: Electrocardiographic (ECG) assessments were available for 100, 64, 41, and 27 patients at baseline, 2-, 4-, and 8-week follow-up, respectively. At baseline prior to initiation of methadone, 28 (28%) patients had QTc prolongation. Clinically significant increase in QTc occurred in only 1 of 64 (1.6%) patients at week 2, and none at weeks 4 and 8. There was no clinical evidence of torsades de pointes, ventricular fibrillation, or sudden death. QTc prolongation was more frequent among patients with increased baseline QTc interval., Conclusions: Baseline QTc prolongation was common, whereas significant QTc interval 500 ms or more after methadone initiation rarely occurred, with no evidence of clinically significant arrhythmias. This study supports the safety of methadone use for pain control in patients with advanced cancer in the palliative care setting.

Background: The goal of this study is to report the safety and efficacy of pancreatic resection for isolated metastatic cancers from nonpancreatic primary disease., Methods: We retrospectively identified patients from a single institution's prospectively gathered pancreaticobiliary database from 1970 to 2007 who underwent a pancreatic resection for metastatic disease., Results: Forty-nine patients were identified with metastatic lesions to the pancreas. Pancreaticoduodenectomy, distal pancreatectomy, and total pancreatectomy were performed in 31, 14, and 4 patients, respectively. Pathology distribution was as follows: 21 renal cell carcinoma (RCC), 6 gallbladder cancer, 4 lung cancer, 4 ovarian cancer, 4 sarcoma, 3 melanoma, 2 colon cancer, 1 breast cancer, 1 hepatocellular carcinoma, 1 seminoma, 1 Langerhans cell histiocytosis, and 1 nonpancreatic endocrine cancer. Postoperative morbidity was 48%. There were no perioperative deaths. A statistically significant difference in survival was found between cancer types (P = .007) with median survivals ranging from 4.8 years for RCC to .9 years for melanoma. Univariate analysis demonstrated a survival disadvantage for patients with perineural (hazard ratio [HR] = 5.4, P = .004) and vascular invasion (HR = 4.4, P = .002). The most commonly resected metastatic lesion of the pancreas was RCC. Eighteen of the 23 patients with RCC had a metachronous lesion with a median length between initial operation and pancreatic resection of 9.3 years. Metachronous lesions had a survival similar to that of synchronous lesions (HR = 1.0, P = .98). Vascular invasion (HR = 2.4, P = .007) and lymph node metastases (HR = 24.1, P = .01) were associated with greater mortality., Conclusion: Long-term survival can be achieved in patients undergoing resection of isolated metastases to the pancreas.

Y-box-binding protein-1 (YB-1) is a multifunctional protein involved in the regulation of transcription, translation, and mRNA splicing. In recent years, several laboratories have demonstrated that YB-1 is directly involved in the cellular response to genotoxic stress. Importantly, YB-1 is increased in tumor cell lines resistant to cisplatin, and the level of nuclear expression of YB-1 is predictive of drug resistance and patient outcome in breast tumors, ovarian cancers, and synovial sarcomas. YB-1 binds to several DNA repair enzymes in vitro including human endonuclease III (hNTH1). Human NTH1 is a bifunctional DNA glycosylase/apurinic/apyrimidinic lyase involved in base excision repair. In this study, we show that YB-1 binds specifically to the auto-inhibitory domain of hNTH1, providing a mechanism by which YB-1 stimulates hNTH1 activity. Indeed, YB-1 strongly stimulates in vitro the activity of hNTH1 toward DNA duplex probes containing oxidized bases, lesions prone to be present in cisplatin treated cells. We also observed an increase in YB-1/hNTH1 complex formation in the mammary adenocarcinoma MCF7 cell line treated with UV light and cisplatin. Such an increase was not observed with mitomycin C or the topoisomerase I inhibitor camptothecin. Accordingly, antisense RNAs against either YB-1 or hNTH1 increased cellular sensitivity to UV and cisplatin but not to mitomycin C. An antisense RNA against YB-1 increased camptothecin sensitivity. In contrast, an antisense against hNTH1 did not. Finally, siRNA against hNTH1 re-established cytotoxicity in otherwise cisplatin-resistant YB-1 overexpressing MCF7 cells. These data indicate that hNTH1 is a relevant target to potentiate cisplatin cytotoxicity in YB-1 overexpressing tumor cells.

Cancer-related fatigue (CRF) is the most common symptom experienced by patients with cancer. Clinically important improvement in the intensity of fatigue in palliative care patients has not been well established. We reviewed the data from 3 clinical trials of fatigue in 194 patients receiving palliative care treatment. Patients completed the Functional Assessment for Chronic Illness Therapy Fatigue (FACIT-F) and Edmonton Symptom Assessment System (ESAS) at baseline and day 8 and their global perception of fatigue improvement (Global benefit score [GBS]: 1 = not beneficial, 7 = greatly important] during day 8. A GBS of 4 or more (moderate improvement, consistently beneficial) was considered a clinically significant improvement. Change scores in the ESAS and FACIT-F from baseline to day 8 were compared to the GBS greater than 4. Receiver-operating characteristic curves were also derived for ESAS and FACIT-F change scores for a GBS greater than 4, greater than 5, and greater than 6. Results showed the mean patient age was 56 (+/-12) years, and 37% were men. A reduction of approximately 10 points in FACIT-F (sensitivity = 73%, specificity = 78%, area under the curve = 0.82) and 4 points in ESAS fatigue (sensitivity = 66%, specificity = 72%, area under the curve = 0.78) score was best able to predict a clinically important improvement (GBS >/= 4). We were able to characterize the relationship between FACIT-F and ESAS scores and patients' global perception of improvement but further studies are needed to validate our findings.

Background: Palliative care services provide symptom control and psychosocial support for dying patients and their families. These services are not available in many cancer centers and tertiary hospitals. The purpose of this study was to review the impact of a palliative care program, established in 1999, on overall in-hospital mortality., Methods: We reviewed the M. D. Anderson Cancer Center computerized database to determine the total number of deaths and discharges and the place of death for each fiscal year from 1999 to 2004. The median length of stay for patients who died in different locations within the hospital was calculated. Annual palliative care consultations for patients who subsequently died in the hospital were retrieved. The annual mortality rate for the cancer center was calculated., Results: The overall in-hospital mortality rates were 3.6, 3.7, 3.6, 3.5, 3.6, and 3.7% of all discharges for the period 1999-2004 respectively (p > 0.2). The number of deaths in the medical intensive care unit (MICU) dropped from 252 in 671 (38%) in 1999 to 213 in 764 (28%) in 2004 (p < 0.0001). Involvement of the palliative care service in the care of patients dying in the hospital grew from 8 in 583 (1%) in 1999 to 264 in 764 (35%) in 2004 (p < 0.0001). The median length of hospital stay (MLOS) for patients who subsequently died in-hospital was significantly longer than that for patients who were discharged alive., Conclusions: Increased involvement by the palliative care service in the care of decedent patients was associated with a decreased MICU mortality and no change in overall hospital mortality rate or inpatient length of hospital stay.

Purpose: The number of patients receiving chemotherapy near the end of life is increasing, as are concerns about goals of treatment, toxicity, and costs. We sought to determine the available sources of knowledge, the choices, and concerns of actual patients, and how patients balanced competing issues., Methods: We used a literature search from 1980 to present., Results: Available patient sources provide little information about prognosis, choices, alternatives, consequences, or how to choose. Many patients would choose chemotherapy for a small benefit in health outcomes, and for a smaller benefit than perceived by their health care providers for their own treatment. Adverse effects are less a concern for patients than for their well health care providers. There are no decision aids to assist patients with metastatic disease in making their choices, such as there are for adjuvant breast therapy., Conclusion: The perspective of the patient is different from that of a well person. Patients are willing to undergo treatments that have small benefits with major toxicity. Receiving realistic information about the different options of care and the likelihood of successful treatment or adverse effects is difficult. These factors may explain some of the increased use of chemotherapy near the end of life. Decision aids and honest, unbiased sources to inform patients of their prognosis, choices, consequences, typical outcomes, and ways to make decisions are needed. More prospective information about how patients make their choices, and what they would consider a good choice, would assist informed decision making.

A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as apoptosis-inducing agents through our cell-based apoptosis screening assay. Several analogues from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-126303, and MX-116407, were synthesized and further characterized. MX-116407, a lead compound from this series, induced apoptosis with an EC50 of 50 nmol/L and inhibited cell growth with a GI50 of 37 nmol/L in T47D breast cancer cells. Treatment of cells with these analogues led to G2-M arrest, cleavage of essential proapoptotic caspase substrates, and induction of nuclear fragmentation. We identified these compounds as tubulin destabilizers with binding site at or close to the colchicine binding site. Compounds in this series were also active in drug-resistant cancer cell lines with a GI50 value for one of the analogues (MX-58151) of 2.5 nmol/L in paclitaxel-resistant, multidrug-resistant MES-SA/DX5 tumor cells. This series of compounds displayed high selectivity against proliferating versus resting cells. Interestingly, these compounds were shown to disrupt preformed endothelial cell capillary tubules in vitro and affect functional vasculature to induce tumor necrosis in vivo and are thus likely to work as tumor vasculature targeting agents. Among these compounds, MX-116407 showed capillary tubule disruption activity in vitro at concentrations well below the cytotoxic dose. In a separate study, we further characterized the antitumor efficacy and pharmacokinetic profile of this series of compounds and identified MX-116407 as a potent apoptosis-inducing agent with apparent activity as tumor vasculature targeting agent.

Purpose: Inpatient palliative care units are unavailable in most cancer centers and tertiary hospitals. The purpose of this article is to review the outcomes of the first 344 admissions to the Palliative Care Inpatient Service (PCIS) at our comprehensive cancer center., Patients and Methods: We retrospectively reviewed our computerized database for clinical and demographic information, length of stay, and hospital billing during the first year of the service's operation., Results: Three hundred twenty patients were admitted during the study period. Their median age was 57 years. The main cancer diagnoses were thoracic or head and neck (44%), gastrointestinal (25%), and hematologic malignancy (8%). The main referral symptoms were pain (44%), nausea (41%), fatigue (39%), and dyspnea (38%). The median length of stay in the PCIS was 7 days (range, 1 to 58 days). Fifty-nine patients died while in the PCIS. However, the overall hospital mortality rate was not increased compared with that in the year before the establishment of the PCIS (3.58% v 3.59%). The mean reimbursement rate for all palliative care charges was approximately 57%, and the mean daily charges in the PCIS were 38% lower than the mean daily charges for the rest of the hospital. Symptom intensity data showed severe distress on admission and significant improvement in the main target symptoms. Most patients were discharged to a hospice., Conclusion: The PCIS has been accepted in our tertiary cancer center on the basis of its clinical utility and financial viability.

Breakthrough pain is a well recognized but ill-defined phenomenon that occurs commonly in the presence of otherwise stable, persistent pain. It is defined now as a "transient pain episode that occurs, or breaks through from the otherwise stable background pain." Breakthrough pain is usually associated with moderate to severe pain and may form a predictor of poor response to treatment with routine pharmacotherapy. Breakthrough pain is also associated with functional impairment and psychological distress. The assessment and treatment should be multidimensional. Although primary therapies such as chemotherapy, radiation treatment, and surgical options are explored, the mainstay of treatment is pharmacotherapy. Nonpharmacologic methods, such as orthotic devices and joint stabilizations along with behavioral methods, should be explored. Anesthetic and neurosurgical procedures are performed on a limited number of patients based on the prognosis, intractable nature of pain, and favorable risk/benefit ratio. Newer oral transmucosal fentanyl offers a favorable pharmacokinetic and pharmacodynamic profile and ease of administration.

Neural blockade, like other accepted treatments for persistent pain, is not a panacea. Careful assessment is required to elicit the need for complementary interventions, including pharmacological management and psychobehavioral and rehabilitative approaches, combined with attention to the palliation of other symptoms. Celiac and superior hypogastric plexus blocks are well-accepted, effective, and minimally hazardous means for providing palliation of visceral abdominopelvic pain. Although they require radiological imaging, they are relatively undemanding of the experienced anesthesiologist pain specialist and do not deplete patients' limited resources and energy. Because of their uniquely favorable risk:benefit ratio, these procedures should be considered early in the course of treating patients with abdominopelvic pain that is expected to persist.

Background: Thrombocytopenia is frequently encountered in patients with cancer. It is associated with an increased risk for clinically important bleeding episodes, which increases the demand for platelet transfusion., Objective: To assess hematopoietic response to and clinical tolerance of recombinant human thrombopoietin, a recently cloned novel cytokine., Design: Phase I and II clinical cohort study., Setting: The University of Texas M.D. Anderson Cancer Center, Houston, Texas., Patients: 12 patients with sarcoma who had high risk for severe chemotherapy-induced thrombocytopenia., Intervention: A single intravenous dose of thrombopoietin (0.3 to 2.4 micrograms/kg of body weight) 3 weeks before chemotherapy., Measurements: Peripheral blood and bone marrow evaluation before and after thrombopoietin administration., Results: A single dose of thrombopoietin was associated with an increase in platelet counts (mean increase from baseline, 61% to 213%; P = 0.002) in a dose-related manner. This increase began by day 4 in most patients and peaked on a median of day 12. This sustained response was associated with a prolonged serum thrombopoietin half life (20 to 30 hours). The platelets appeared morphologically normal and showed normal aggregation in response to various agonists. Platelet response was accompanied by a dose-related increase in bone marrow megakaryocytes (as much as 4-fold); the expansion of the bone marrow progenitors of myeloid, erythroid, multipotential, and megakaryocytic lineages; and the marked mobilization of progenitors (maximum, 5.7-fold to 10-fold) of multiple cell lineages in the peripheral blood. Treatment was well tolerated, and no serious adverse events occurred., Conclusions: Thrombopoietin, administered as a single dose, is a potent stimulus for prolonged platelet production in humans. It merits further evaluation for the prevention and treatment of thrombocytopenia.

Because interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) act synergistically in vitro in the generation of lymphokine-activated killer (LAK) cells. we initiated a clinical trial of these lymphokines in combination. Twenty patients with advanced malignancy were treated at fixed dose levels of recombinant IFN-gamma given by intramuscular (i.m.) injections once a day and recombinant IL-2 given by an intravenous (i.v.) bolus injection 3 times a day for 7 days after a 3-day treatment with fixed doses (250 micrograms/m2/day) of IFN-gamma alone. A minimum of four patients were treated at each of the four dose levels studied. The side effects of the combination therapy were similar to those seen with individual lymphokines and included fever and chills, myalgia, headache, fatigue, nausea. vomiting, peripheral edema, skin rash, and hypotension. The maximum tolerated dose for the combination after a fixed dose of IFN-gamma was 2 x 10(5) U/M2/day (10 micrograms/m2/day) of IFN-gamma and 3 x 10(6) U/M2/day of IL-2, with fluid retention as the dose-limiting toxicity. Whereas natural killer (NK) or LAK activity or both were significantly increased in four of eight patients studied, only one patient with renal cell cancer had a minor response for four treatment cycles. We conclude that combination therapy with cytokines IL-2 and IFN-gamma given in this schedule had manageable toxicity and exhibited immunomodulatory effects in some patients but had no significant antitumor activity in this patient population.

While fairly complete and reliable incident data on childhood cancers are available from the registries in India, mortality and survival information is not. Information concerning the latter was obtained by the Bangalore cancer registry through active follow-up involving visits to homes of patients. Between 1982 and 1989, 617 cases of cancers in childhood were registered, giving an age-standardized incidence rate of 84.8 and 48.4 per million in male and female children, respectively. Active follow-up provided mortality/survival information in 532 or 86.2 percent of these cases. Overall, observed five-year survival was 36.8 percent (both genders combined) with a relative survival of 37.5 percent when childhood mortality in the general population was taken into account. The five-year relative survival was best for thyroid carcinoma (100 percent) followed by Hodgkin's disease (73 percent) and retinoblastoma (72.9 percent). Survival was comparatively low, being 9.9 percent in acute nonlymphatic leukemia and less than 20 percent in rhabdomyosarcoma and the category grouped as 'other malignant neoplasms.' Survival in Hodgkin's disease was influenced by clinical stage at presentation, but was not statistically significant possibly due to small numbers.

Effective control of cancer pain can now be achieved in a high proportion of patients with rigorously applied pharmacologic treatment, reducing the need for more demanding invasive procedures. Ten to thirty percent of patients will, however, require some form of more aggressive management, ranging from the parenteral and spinal administration of opioids to neurodestructive procedures. Intrathecal neurolysis is a time-tested procedure that, although used less frequently than in the past, still has important indications. Guidelines for patient selection and results of a recent clinical series are presented here.

Peripheral eosinophilia is a rare but recognized accompaniment of malignant disease. Two unusual cases, one with a histiocytic lymphoma and the other with cervical carcinoma, are described. In the first patient, pulmonary infiltrates developed at the height of the eosinophilia and in the second, the peripheral eosinophilia heralded the onset of disseminated disease. Tumor-associated peripheral eosinophilia is reviewed, and it is concluded that peripheral eosinophilia associated with a malignant setting is a marker of extensive disease and is thus associated with a poor prognosis.