BACKGROUND: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival.
METHODS: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140).
FINDINGS: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6-6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9-90·7) in the 6-month group and 89·8% (88·3-91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93-1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001).
INTERPRETATION: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial.
FUNDING: UK National Institute for Health Research, Health Technology Assessment Programme.

BACKGROUND: Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer.
METHODS: In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events.
RESULTS: A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group.
CONCLUSIONS: Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).

BACKGROUND: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population.
METHODS: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival.
RESULTS: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 10
CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).

BACKGROUND: Pulmonary computed tomography (CT) scans are commonly used as part of the clinical criteria in diagnostic workup of invasive fungal diseases like invasive aspergillosis, and may identify radiographic abnormalities, such as halo signs or air-crescent signs. We assessed the diagnostic utility of CT assessment in patients with hematologic malignancies or those who had undergone allogeneic hematopoietic stem cell transplantation in whom invasive aspergillosis was suspected.
METHODS: This post-hoc analysis assessed data from a prospective, multicenter, international trial of voriconazole (with and without anidulafungin) in patients with suspected invasive aspergillosis (IA; proven, probable, or possible, using 2008 European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria) [NCT00531479]. Eligible patients received at least one baseline lung CT scan.
RESULTS: Of 395 patients included in this post-hoc analysis, 240 patients (60.8%) had 'confirmed' proven (9/240, 3.8%) or probable (231/240, 96.3%) invasive aspergillosis (cIA) and 155 patients (39.2%) had 'non-confirmed' invasive aspergillosis (all nIA; all possible IA (de Pauw et al., Clin Infect Dis 46:1813-21, 2008)). Mean age was 52.3 and 50.5 years, 56.3 and 60.0% of patients were male, and most patients were white (71.7 and 71.0%) in the cIA and nIA populations, respectively. Median baseline galactomannan was 1.4 (cIA) and 0.2 (nIA), mean Karnofsky score was 65.3 (cIA) and 66.8 (nIA), and mean baseline platelet count was 48.0 (cIA) and 314.1 (nIA). Pulmonary nodules (46.8% of all patients), bilateral lung lesions (37.5%), unilateral lung lesions (28.4%), and consolidation (24.8%) were the most common radiographic abnormalities. Ground-glass attenuation (cIA: 24.2%; nIA: 11.6%; P < 0.01) and pulmonary nodules (cIA: 52.5%; nIA: 38.1%; P < 0.01) were associated with cIA. Other chest CT scan abnormalities (including halo signs and air-crescent signs) at baseline in patients with hematologic malignancy or hematopoietic stem cell transplantation, and suspected IA, were not associated with cIA.
CONCLUSIONS: These findings highlight the limitations in the sensitivity of chest CT scans for the diagnosis of IA, and reinforce the importance of incorporating other available clinical data to guide management decisions on individual patients, including whether empirical treatment is reasonable, pending full evaluation.
TRIAL REGISTRATION: NCT00531479 (First posted on ClinicalTrials.gov on September 18, 2007).

BACKGROUND: Trefoil Factor 3 (TFF3) has been implicated in Prostate Cancer (PCa) progression. However, its prognostic value and association with other biomarkers have not been fully explored. We assessed the combined value of TFF3 and PTEN in two cohorts: one is managed surgically for localized PCa and the second is managed non-surgically by androgen deprivation therapy for advanced disease.
DESIGN: 228 radical prostatectomies (RP) and 318 transurethral resection of prostate (TURP) samples were assessed by immunohistochemistry (IHC) for TFF3 and by IHC and fluorescent in situ hybridization (FISH) for PTEN. Results of biomarkers expression were correlated with various pathological and clinical outcome parameters including biochemical recurrence (BCR) in the RP cohort and cancer-specific mortality (PCSM) and overall survival (OS) in the TURP cohort.
RESULTS: TFF3 expression was detected in 131/226 (57.9%) RP samples and 148/318 (46.5%) of TURP cases. In general, TFF3 positivity was less frequently observed with advanced Gleason Groups. TFF3 expression was also assessed in relation to PTEN expression. Only 15-16% of TFF3-expressed cases were present in association with complete loss of PTEN expression in the TURP and localized cohorts, respectively. Loss of TFF3 expression was not related to BCR after RP, but was prognostic in the non-surgical cohort and associated with decrease OS and PCSM (HR 2.31, CI: 1.67-3.18, p < 0.0001) and (HR 3.99, CI: 2.43-6.56; p < 0.0001), respectively. Adjusting for Gleason score, combined loss of TFF3/PTEN was most associated with OS (HR 2.33, CI: 1.49-3.62; p < 0.0001) and PCSM (HR = 3.44, CI: 1.75-6.78, p < 0.0001).
CONCLUSION: The study documents for the first time significant association for combined status of TFF3 expression and PTEN loss in OS and PCSM in patients not managed by surgical intervention. Prospective assessment of PTEN and TFF3 may provide further insight into molecularly subtyping PCa and aid in stratifying patients at risk for lethal disease.

Spiradenoma and cylindroma are distinctive skin adnexal tumors with sweat gland differentiation and potential for malignant transformation and aggressive behaviour. We present the genomic analysis of 75 samples from 57 representative patients including 15 cylindromas, 17 spiradenomas, 2 cylindroma-spiradenoma hybrid tumors, and 24 low- and high-grade spiradenocarcinoma cases, together with morphologically benign precursor regions of these cancers. We reveal somatic or germline alterations of the CYLD gene in 15/15 cylindromas and 5/17 spiradenomas, yet only 2/24 spiradenocarcinomas. Notably, we find a recurrent missense mutation in the kinase domain of the ALPK1 gene in spiradenomas and spiradenocarcinomas, which is mutually exclusive from mutation of CYLD and can activate the NF-κB pathway in reporter assays. In addition, we show that high-grade spiradenocarcinomas carry loss-of-function TP53 mutations, while cylindromas may have disruptive mutations in DNMT3A. Thus, we reveal the genomic landscape of adnexal tumors and therapeutic targets.

Understanding the risk factors that initiate cancer is essential for reducing the future cancer burden. Much of our current cancer control insight is from cohort studies and newer large-scale population laboratories designed to advance the science around precision oncology. Despite their promise for improving diagnosis and treatment outcomes, their current reductionist focus will likely have little impact shifting the cancer burden. However, it is possible that these big data assets can be adapted to have more impact on the future cancer burden through more focus on primary prevention efforts that incorporate artificial intelligence (AI) and machine learning (ML). ML automatically learns patterns and can devise complex models and algorithms that lend themselves to prediction in big data, revealing new unexpected relationships and pathways in a reliable and replicable fashion that otherwise would remain hidden given the complexities of big data. While AI has made big strides in several domains, the potential application in cancer prevention is lacking. As such, this commentary suggests that it may be time to consider the potential of AI within our existing cancer control population laboratories, and provides justification for why some small targeted investments to explore their impact on modelling existing real-time cancer prevention data may be a strategic cancer control opportunity.

Trastuzumab is integral to HER2+ cancer treatment, but its therapeutic index is narrowed by the development of resistance. Phosphorylation of the translation initiation factor eIF2α (eIF2α-P) is the nodal point of the integrated stress response, which promotes survival or death in a context-dependent manner. Here, we show an anti-tumor function of the protein kinase PKR and its substrate eIF2α in a mouse HER2+ breast cancer model. The anti-tumor function depends on the transcription factor ATF4, which upregulates the CDK inhibitor P21

Capicua (Cic) is a transcriptional repressor mutated in the brain cancer oligodendroglioma. Despite its cancer link, little is known of Cic's function in the brain. We show that nuclear Cic expression is strongest in astrocytes and neurons but weaker in stem cells and oligodendroglial lineage cells. Using a new conditional Cic knockout mouse, we demonstrate that forebrain-specific Cic deletion increases proliferation and self-renewal of neural stem cells. Furthermore, Cic loss biases neural stem cells toward glial lineage selection, expanding the pool of oligodendrocyte precursor cells (OPCs). These proliferation and lineage effects are dependent on de-repression of Ets transcription factors. In patient-derived oligodendroglioma cells, CIC re-expression or ETV5 blockade decreases lineage bias, proliferation, self-renewal, and tumorigenicity. Our results identify Cic as an important regulator of cell fate in neurodevelopment and oligodendroglioma, and suggest that its loss contributes to oligodendroglioma by promoting proliferation and an OPC-like identity via Ets overactivity.

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk. Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study. We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis. This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified. Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children. Pathogenesis of RMS is associated with aggressive growth pattern and increased risk of morbidity and mortality. There are two main subtypes or RMS: embryonal and alveolar. The embryonal type is characterized by distinct molecular aberrations, including alterations in the activity of certain protein kinases. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays a vital role in focal adhesion (FA) assembly to promote cytoskeleton dynamics and regulation of cell motility. It is regulated by multiple phosphorylation sites: tyrosine 397, Tyr 576/577, and Tyr 925. Tyrosine 397 is the autophosphorylation site that regulates FAK localization at the cell periphery to facilitate the assembly and formation of the FA complex. The kinase activity of FAK is mediated by the phosphorylation of Tyr 576/577 within the kinase domain activation loop. Aberrations of FAK phosphorylation have been linked to the pathogenesis of different types of cancers. In this regard, pY397 upregulation is linked to increase ERMS cell motility, invasion, and tumorigenesis.
METHODS: In this study, we have used an established human embryonal muscle rhabdomyosarcoma cell line RD as a model to examine FAK phosphorylation profiles to characterize its role in the pathogenies of RMS.
RESULTS: Our findings revealed a significant increase of FAK phosphorylation at pY397 in RD cells compared to control cells (hTERT). On the other hand, Tyr 576/577 phosphorylation levels in RD cells displayed a pronounced reduction. Our data showed that Y925 residue exhibited no detectable change. The in vitro analysis showed that the FAK inhibitor, PF-562271 led to G1 cell-cycle arrest induced cell death (IC
CONCLUSIONS: The data presented herein indicate that targeting FAK phosphorylation at distinct sites is a promising strategy in future treatment approaches for defined subgroups of rhabdomyosarcoma.

BACKGROUND: Melanoma is a high fatality skin cancer which lacks effective drugs. Sasanquasaponin, an important sort of constituents in theaceae, has been demonstrated to have potent anti-tumor effect in breast cancer and hepatocellular carcinoma. As a sasanquasaponin, we speculate that Sasanquasaponin III (SQS III) isolated from Schima crenata Korth may also have anti-tumor activity.
PURPOSE: This study aims to investigate whether SQS III has anti-melanoma activity and examine the underlying mechanisms of SQS III against melanoma.
METHODS/STUDY DESIGNS: The anti-proliferative effect of SQS III was assessed by cells viability assay. Annexin V-FITC/PI double staining assay was utilized for detection of apoptosis. Mitochondrial membrane potential and reactive oxygen species (ROS) production were detected using JC-1 and DCFH-DA assay, respectively. Autophagy was monitored using transmission electron microscopy (TEM) and GFP-LC3 transfection fluorescence analysis. Autophagosome-lysosome fusion and lysosomal degradation were determined using a GFP-LC3 & LAMP1 co-localization assay and DQ-BSA staining. Proteins related to apoptosis and autophagy were analyzed by Western blotting.
RESULTS: Our results demonstrated that the SQS III exhibited potent anti-cancer activity in A375 cells by inducing both apoptosis and autophagy. In melanoma cells treated with SQS III, caspases were activated and PARP was cleaved, proving the occurrence of apoptosis. Mechanistic studies indicated that the pro-apoptosis activity of SQS III was mediated by death receptor pathway and mitochondrial dysfunction which was induced by ROS accumulation and reversed by the ROS inhibitor N-acetyl-cysteine (NAC). In addition to triggering apoptosis, SQS III may also cause autophagy in melanoma cells. Our results demonstrated that SQS III induced up-regulated expression of GFP-LC3, autophagosome-lysosomal fusion and lysosomal degradation. Additionally, the ROS accumulation was also involved in the activation of autophagy. Meanwhile, it was also found that after SQS III treatment, the expression of LC3-II was up-regulated and the AKT/mTOR signaling pathway was inhibited. The autophagy inhibitor 3-MA converted cytotoxicity and apoptosis of SQS III in A375 cells, which indicated that autophagy promoted the SQS III-induced apoptosis.
CONCLUSION: SQS III showed potent anti-cancer activity by inducing apoptosis and autophagy, which provides insights into its possible use as a therapy for melanoma.

Previous studies have linked systemic glucocorticoid use with intestinal perforation. However, the association between intestinal perforation and endogenous hypercortisolism has not been well described, with only 14 previously published case reports. In this study, we investigated if intestinal perforation occurred more frequently in patients with ectopic ACTH syndrome and in those with a greater than 10-fold elevation of 24-hour urinary free cortisol level. Of 110 patients with ACTH-dependent Cushing's syndrome followed in two clinics in Canada, six cases with intestinal perforation were identified over 15 years. Age of patients ranged from 52 to 72, five females and one male, four with Cushing's disease and two with ectopic ACTH production, one from a pancreatic neuroendocrine tumor and one from medullary carcinoma of the thyroid. Five had diverticular perforation and one had intestinal perforation from a stercoral ulcer. All cases had their lower intestinal perforation when the cortisol production was high, and one patient had diverticular perforation 15 months prior to the diagnosis of Cushing's disease. As in previously reported cases, most had hypokalemia and abdominal pain with minimal or no peritoneal symptoms and this occurred during the active phase of Cushing's syndrome. Whereas all previously reported cases occurred in patients with 24-hour urinary free cortisol levels greater than 10-fold the upper limit of normal when measured and 11 of 14 patients had ectopic ACTH production, only one of our patients had this degree of hypercortisolism and four of our six patients had Cushing's disease. Similar to exogenous steroid use, patients with endogenous hypercortisolism also have a higher risk of intestinal, in particular diverticular, perforation and should be monitored closely for its occurrence with a low threshold for investigation and surgical intervention. Elective colonoscopy probably should be deferred until Cushing's syndrome is under control.

Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.

Body contour changes are commonly seen in prostate and head and neck (H&N) patients undergoing volumetric modulated arc therapy (VMAT) treatments, which may cause a discrepancy between the planned dose and the delivered dose. Dosimetrists, radiation oncologists or medical physicists sometimes are required to visually assess the dosimetric impact of body contour changes and make a judgment call on whether further re-assessment of the plan is needed. However, an intuitive judgment cannot always be made in a timely manner due to the complexity of VMAT plans as well as the complicated forms of body contour changes. This study evaluated the dosimetric effect of body contour changes for prostate and H&N patients to help with clinical decision-making. By analyzing the one-dimensional spatial dose profiles from the original body and the body with different body contour deformations, rules of thumb for dose percentage change and isodose line shift due to body contour changes were ascertained. Moreover, based on dose distribution comparison using three-dimensional gamma analysis, the response of the clinical prostate and H&N VMAT plans to body contour changes was assessed. Within center specific dose deviation tolerances, prostate patients who had less than 2 cm single side body contour change or less than 1 cm uniform body contour change were unlikely to need plan re-assessment; H&N VMAT plans with less than 1 cm uniform body contour change or less than 1 cm shoulder superior-inferior positional change were also unlikely to trigger further evaluation. Dose percentage change and isodose line shift were considered independently from the problem of volume changes in this study, but clinically, both aspects must be considered.

Aims: Death-associated protein kinase-1 (DAPK1) is a pro-apoptotic Ser/Thr kinase that participates in cell apoptosis and tumor suppression. DAPK1 is frequently lost in many different tumor types including breast cancer. The aim of this study was to evaluate the promoter methylation status of DAPK1 and a possible correlation with the expression of DAPK1 and standard clinicopathological features in invasive ductal breast carcinoma patients (IDC). Methods: Methylation Specific PCR (MSP) was carried out to investigate the promoter methylation status of DAPK1 from 128 breast cancer patients. The effect of promoter methylation on protein expression was evaluated by immunohistochemistry (n=128) and western blotting (n=56). Results: We found significant difference in DAPK1 promoter methylation frequency among breast tumors when compared with the corresponding normal tissues. Hypermethylation of DAPK1 is significantly correlated with the loss of DAPK1 protein expression (P < .001, rs= -0.361). The loss of DAPK1 protein was significantly associated with estrogen receptor (ER) negativity (p= 0.003), triple negative breast cancer (TNB) (p= 0.024) and advanced tumor stages (P = 0.001). Moreover, age at diagnosis (p= 0.041), tumor stage (p= 0.034), ER negativity (p= 0.004) and TNB cancers (p=0.003) correlated significantly with the hypermethylation of the DAPK1 promoter. Coclusion: This study indicates that DAPK1 is methylated in IDC and promoter hypermethylation could be attributed to silencing of DAPK1 gene expression in breast cancer. Thus, we consider DAPK1 inactivation by promoter hypermethylation likely plays a role in the development and progression of breast cancer.

PURPOSE: In this systematic review and meta-analysis, we aimed to estimate cancer-specific mortality and all-cause mortality among cancer survivors associated with both short (typically 5 or 6 h/night) and long (typically 9 or 10 h/night) sleep duration (versus recommendations), separately by sex, cancer site, and sampling frame.
METHODS: We completed a systematic literature search in five databases and captured relevant literature published through December 2018. Two reviewers independently screened 9,823 records and 32 studies were included representing over 73,000 deaths in cancer survivors. Estimates for short and long sleep duration compared to 'recommended' were pooled using random-effects models.
RESULTS: Pooled hazards ratios for short and long sleep duration for all-cancer-specific mortality were 1.03 (95% CI 1.00-1.06) and 1.09 (95% CI 1.04-1.13), respectively. In subgroup analyses by cancer site, statistically significant increased risks were found for both short and long sleep durations for lung cancer-specific mortality. These associations were maintained when stratified by sex and sampling frame. There were no statistically significant associations found between either short or long sleep duration and breast, colorectal, ovarian, or prostate cancer-specific mortality. Statistically significant increases in all-cause mortality were observed with long sleep duration in breast cancer survivors (1.38; 95% CI 1.16-1.64) with no significant associations found for colorectal or liver/pancreatic cancers.
CONCLUSIONS: We observed that long sleep duration increases cancer-specific mortality for all-cancers and lung cancers, while all-cause mortality is increased for breast cancer survivors. Limitations were found within the existing literature that need to be addressed in future studies in order to improve the understanding regarding the exact magnitude of the effect between sleep duration and site-specific mortality.

AIM: To assess whether clinical trial participation affects survival outcomes of radiotherapy-treated localized prostate cancer patients compared with similar treatment within a real-world setting.
METHODS: This is a comparative analysis of the outcomes of localized prostate cancer patients treated within two clinical trials (NCT00331773; NCT00004054) versus the outcomes of similar cohorts of patients registered within the SEER database and treated with radiotherapy. Propensity score matching was conducted to account for heterogeneity in background patient information. Within the postmatching cohort, Kaplan-Meier survival according to treatment setting was reconducted. Moreover, an assessment of the impact of treatment setting on overall survival (OS) was conducted in a multivariate Cox regression model adjusted for age, race, ethnicity, T-stage, PSA and Gleason score.
RESULTS: A total of 5209 low-risk patients and 2115 high-risk patients were included in the current analysis. For both low- and high-risk disease, Kaplan-Meier analysis for OS in the postmatching cohort did not show any difference in OS between patients treated within clinical trial setting versus patients treated within SEER database (p = 0.176; p = 0.097; respectively). Likewise in multivariate Cox regression analysis, treatment context (clinical trial vs SEER) does not affect OS for either low- or high-risk disease (p = 0.470; p = 0.412; respectively).
CONCLUSION: After accounting for possible confounders in baseline characteristics, there was no conclusive evidence of a survival difference between localized prostate cancer patients treated with external beam radiotherapy within routine, real-world settings compared with patients treated within clinical trials.

OBJECTIVES: To evaluate trends in uptake of sentinel lymph node (SLN) procedures over time and associated factors in women with vulvar cancer.
METHODS: A retrospective population-based cohort study identified women with invasive squamous cell carcinoma (SCC) of the vulva using health administrative data for the province of Ontario, Canada, between 2008 and 2016. Patients who underwent SLN procedures were compared to those who had groin node dissection (GND). Multivariable analysis was used to identify factors associated with SLN procedures.
RESULTS: 1385 patients with SCC of the vulva were identified; 1079 had a surgical procedure. Only those with groin node assessment were included in the study cohort (n = 732, 68%). SLN procedures were done in 52%. When comparing SLN versus GND, the rate of SLNs was significantly different by year of diagnosis (P < 0.001), associated comorbidity (P < 0.001) and institution (P < 0.0001). The rates of SLNs by institution with gynecologic oncologist were variable and ranged from 32% to 79% among 9 centers. There were no differences in age, income quintile, and urban/rural residence. The proportion of SLN procedures increased from 30.1% (CI 18.9-45.6) in 2008 to 65.2% (CI 36.5-107.6) in 2016. On multivariate analysis, factors significantly associated with SLN procedures were more recent year of diagnosis (OR 7.9, CI 2.7-23.5) associated comorbidities (OR 2.7, CI 1.5-5.0) and institution (Site 5, OR 19.6 [CI 3.6-108.3] and Site 6, [OR 6, CI 1.1-33.4]).
CONCLUSIONS: The proportion of SLN procedures in women with vulvar cancer has increased over time, but uptake is not uniform across institutions. Barriers to uptake should be explored.

OBJECTIVES: To identify events during a child's cancer trajectory when parents perceived their marriage/partnership to be most strengthened and/or challenged.
RESEARCH APPROACH: Using a cross-sectional qualitative design, participants completed a self-administered questionnaire addressing changes in their relationship during their child's cancer trajectory, including events perceived to strengthen/challenge their relationship, and recommendations for other parents.
PARTICIPANTS: 192 parents of pediatric oncology patients across three institutions. Data were analyzed using qualitative content analysis.
FINDINGS: Themes included relationship-specific, illness experience-related, and external supports/stressors that impacted the relationship. Dyadic strategies, empathic communication, and supportive behaviors strengthened the couple's relationship, whereas physical and emotional distance most commonly challenged the relationship. Recommendations to other parents included open communication, couple's connectedness, and use of external supports.
INTERPRETATION: Offering psychosocial support and helping parents anticipate when their relationship can be strengthened/challenged can be an important part of ongoing care. Implications for psychosocial providers: Teaching communication and dyadic coping strategies can help parents manage stress and build cohesion.

BACKGROUND: Recurrence is not explicitly documented in cancer registry data that are widely used for research. Patterns of events after initial treatment such as oncology visits, re-operation, and receipt of subsequent chemotherapy or radiation may indicate recurrence. This study aimed to develop and validate algorithms for identifying breast cancer recurrence using routinely collected administrative data.
METHODS: The study cohort included all young (≤ 40 years) breast cancer patients (2007-2010), and all patients receiving neoadjuvant chemotherapy (2012-2014) in Alberta, Canada. Health events (including mastectomy, chemotherapy, radiation, biopsy and specialist visits) were obtained from provincial administrative data. The algorithms were developed using classification and regression tree (CART) models and validated against primary chart review.
RESULTS: Among 598 patients, 121 (20.2%) had recurrence after a median follow-up of 4 years. The high sensitivity algorithm achieved 94.2% (95% CI: 90.1-98.4%) sensitivity, 93.7% (91.5-95.9%) specificity, 79.2% (72.5-85.8%) positive predictive value (PPV), and 98.5% (97.3-99.6%) negative predictive value (NPV). The high PPV algorithm had 75.2% (67.5-82.9%) sensitivity, 98.3% (97.2-99.5%) specificity, 91.9% (86.6-97.3%) PPV, and 94% (91.9-96.1%) NPV. Combining high PPV and high sensitivity algorithms with additional (7.5%) chart review to resolve discordant cases resulted in 94.2% (90.1-98.4%) sensitivity, 98.3% (97.2-99.5%) specificity, 93.4% (89.1-97.8%) PPV, and 98.5% (97.4-99.6%) NPV.
CONCLUSION: The proposed algorithms based on routinely collected administrative data achieved favorably high validity for identifying breast cancer recurrences in a universal healthcare system in Canada.

PURPOSE: Favorable outcomes were achieved for children with acute lymphoblastic leukemia (ALL) with the first Russian multicenter trial Moscow-Berlin (ALL-MB) 91. One major component of this regimen included a total of 18 doses of weekly intramuscular (IM) native Escherichia coli-derived asparaginase (E. coli-ASP) at 10000 U/m
METHODS: Between April 2002 and November 2006, 774 SR patients were registered in 34 centers across Russia and Belarus, 688 of whom were randomized. In arm ASP-5000 (n = 334), patients received 5000 U/m
RESULTS: Probabilities of disease-free survival, overall survival and cumulative incidence of relapse at 10 years were comparable: 79 ± 2%, 86 ± 2% and 17.4 ± 2.1% (ASP-5000) vs. 75 ± 2% and 82 ± 2%, and 17.9 ± 2.0% (ASP-10000), while death in complete remission was significantly lower in arm ASP-5000 (2.7% vs. 6.5%; p = 0.029).
CONCLUSION: Our findings suggest that weekly 5000 U/m

Magnetic drug targeting (MDT) and magnetic-based drug/cargo delivery are emerging treatment methods which attracting the attention of many researchers for curing different cancers and artery diseases such as atherosclerosis. Herein, computational studies are accomplished by utilizing magnetic approaches for cancer and artery atherosclerosis drug delivery, including nanomagnetic drug delivery and magnetic-based drug/cargo delivery. For the first time, the four-layer structural model of the artery tissue and its porosity parameters are modeled in this study which enables the interaction of particles with the tissue walls in blood flow. The effects of parameters, including magnetic field strength (MFS), magnet size, particle size, the initial position of particles, and the relative magnetic permeability of particles, on the efficacy of MDT through the artery walls are characterized. The magnetic particle penetration into artery layers and fibrous cap (the covering layer over the inflamed part of the artery) is further simulated. The MDT in healthy and diseased arteries demonstrates that some of the particles stuck in these tissues due to the collision of particles or blood flow deviation in the vicinity of the inflamed part of the artery. Therefore the geometry of artery and porosity of its layers should be considered to show the real interaction of particles with the artery walls. Also, the results show that increasing the particles/drug/cargo size and MFS leads to more particles/drug/cargo retention within the tissue. The present work provides insights into the decisive factors in arterial MDT with an obvious impact on locoregional cancer treatment, tissue engineering, and regenerative medicine.

Primary bronchial cancer accounts for almost 20% of all cancer death worldwide. One of the emerging techniques with tremendous power for lung cancer therapy is magnetic aerosol drug targeting (MADT). The use of a permanent magnet for effective drug delivery in a desired location throughout the lung requires extensive optimization, but it has not been addressed yet. In the present study, the possibility of using a permanent magnet for trapping the particles on a lung tumor is evaluated numerically in the Weibel's model from G0 to G3. The effect of different parameters is considered on the efficiency of particle deposition in a tumor located on a distant position of the lung bronchi and bronchioles. Also, the effective position of the magnetic source, tumor size, and location are the objectives for particle deposition. The results show that a limited particle deposition occurs on the lung branches in passive targeting. However, the incorporation of a permanent magnet next to the tumor enhanced the particle deposition fraction on G2 to up to 49% for the particles of 7 µm diameter. Optimizing the magnet size could also improve the particle deposition fraction by 68%. It was also shown that the utilization of MADT is essential for effective drug delivery to the tumors located on the lower wall of airway branches given the dominance of the air velocity and resultant drag force in this region. The results demonstrated the high competence and necessity of MADT as a noninvasive drug delivery method for lung cancer therapy.

Due to advances in prevention, early detection and treatment, early breast cancer mortality has decreased by nearly 40% during the last four decades. Yet, the risk of cardiovascular disease (CVD) mortality is significantly elevated following a breast cancer diagnosis, and it is a leading cause of death in this population. This review will discuss the most recent evidence for risks, pathology, mechanisms, and prevention of CVD morbidity and mortality in women with breast cancer. This evidence will be synthesized into a new model 'the compounding risk and protection model.' This model proposes that the balance between risk factors (i.e., older age, pre-existing traditional CVD risk factors and shared biologic pathways for CVD and cancer such as inflammation, as well as treatment-related and lifestyle toxicity) and potential protection factors (i.e., lifelong non-smoking, regular physical activity, a healthy diet rich in fruits and vegetables, and management of body weight and stress, heart failure therapy) determine the individual risk of CVD morbidity and mortality after diagnosis of early breast cancer.

BACKGROUND: Computed tomography-derived body composition parameters are emerging prognostic factors in colorectal cancer.
OBJECTIVE: This study aimed to determine the roles of sarcopenia, myosteatosis, and obesity as independent and overlapping parameters in stage I to III colorectal cancer.
DESIGN: This is a retrospective cohort study from a prospectively collected database. Multivariate Cox proportional hazards models were performed to assess the associations between body composition parameters and survival.
SETTINGS: All patients were seen in a tertiary care cancer center.
PATIENTS: Adult patients with stage I to III colorectal cancer, undergoing curative resection from 2007 to 2009, were included.
INTERVENTION: Computed tomography-derived quantification of skeletal muscle and adipose tissues was used to determine population-specific cutoffs for sarcopenia, myosteatosis, and total adiposity.
MAIN OUTCOME MEASURES: Primary outcome measures were overall, recurrence-free, and cancer-specific survival.
RESULTS: In the 968 patients included, there were a total of 254 disease recurrences and 350 deaths. Body mass index and CT-derived measures of adiposity did not result in worse survival outcomes. Sarcopenia was independently predictive of worse overall (HR, 1.45; 95% CI, 1.16-1.84), recurrence-free (HR, 1.32; 95% CI, 1.00-1.75), and cancer-specific survival (HR, 1.46; 95% CI, 1.09-1.94) in a multivariate model. Myosteatosis was also independently predictive of overall survival (HR, 1.53; 95% CI, 1.19-1.97). In a model considering joint effects of sarcopenia and myosteatosis, the presence of both predicted the worst overall (HR, 2.23; 95% CI, 1.62-3.06), recurrence-free (HR, 1.53; 95% CI, 1.06-2.21), and cancer-specific survival (HR, 2.40; 95% CI, 1.69-3.42) in a multivariate model.
LIMITATIONS: The limitations of this study are inherent in retrospective observational studies.
CONCLUSIONS: Sarcopenia and myosteatosis are independent predictors of worse survival in stage I to III colorectal cancer, and their joint effect is highly predictive of reduced overall, recurrence-free, and cancer-specific survival. See Video Abstract at http://links.lww.com/DCR/A923.

OBJECTIVES: The treatment of hemangiomas in the hypopharynx and larynx can be challenging and stressful because of the high tumor recurrence rate. The objective of this study was to investigate the therapeutic effect of the combination of intratumor injection of bleomycin and electroresection/electrocautery on the hemangiomas in the hypopharynx and larynx through suspension laryngoscopy.
METHODS: With patients under general anesthesia, the hemangiomas were fully exposed through suspension laryngoscopy. After intratumor injection of bleomycin, in some patients, the hemangiomas were completely resected along the bottom of the tumor pedicle by polypus-forceps electroscalpel; for other patients, the hemangiomas were pinched and held, and then the whole-tumor tissues were cauterized and coagulated by the electroscalpel. Prior to commencing the study, all participants signed informed consents, and all procedures were approved by the hospital ethical committee.
RESULTS: There was almost no bleeding during the operations, no postoperative dyspnea, and no hemorrhage. The patients were followed up for 3 years; the 3-year cure rate was 97%.
CONCLUSION: The hemangioma in the hypopharynx and larynx can be cured by a single-session treatment, using the combination of intratumor injection of bleomycin and electroresection/electrocautery through suspension laryngoscopy. Our method is reliable, affordable, and effective, and it could be widely applied in other hospitals.

Long Interspersed Nuclear Element-1 (LINE-1) are DNAs that compromise 17% of our genome. LINE-1 expression is triggered by environmental stressors and accomplished through its demethylation leading to genomic instability. Expression of LINE-1 is regulated in adult somatic tissues through several endogenous defensive mechanisms, but is found to be associated with tumorigenesis in several cancers. This finding, has inspired the use of different indicators of LINE-1 activation, as biomarkers in cancer diagnostics and even therapeutic targets in recent years. The objective of this review is to provide a critical examination of LINE-1 elements as companion cancer diagnostic/prognostic biomarkers and anti-cancer drug targets. In our view, there's great potential for LINE-1 serving at both forefronts, but there is a need for more mechanistic studies in the clinic as well as on the bench research to validate LINE-1 activation elements as cancer biomarkers or therapeutic targets; in different cancer types and/or stages of the disease. In this context, development of minimally invasive, reliable and sensitive diagnostic tools for LINE-1 activation elements for clinical use, is of priority.

Background: The introduction of direct-acting antivirals (DAA) for HCV has led to high rates of HCV eradication. Treatment of patients awaiting liver transplantation (LT) has been controversial. Recent data suggests that DAA treatment may accelerate recurrent HCC. The impact of DAA on delisting for HCC progression or recurrent HCC post-LT has not been well characterized.
Methods: A retrospective review of both waitlist patients and LT recipients at a single institution was performed. Patient demographics, HCV treatment, HCC features and treatments, biopsy results, and graft and patient survival were evaluated. Patients on the LT waitlist or who were transplanted between January 2014 and December 2015 were included. Data was collected through December 2017 to have a minimum of two years of follow-up.
Results: In the study period, 128 adult LT were performed. 44 patients were HCV+, and 68.2% (N=30) also had HCC. 38.6% (N=17) of HCV+ patients received DAA pre-LT, and 94.1% (N=16/17) achieved sustained virologic response (SVR) pre-LT. Among untreated HCV+ patients who underwent LT, 81.5% (N=22/27) received DAA post-LT, with 82.6% achieving SVR post-LT (N=18/22). 82.1% (N=23/28) of untreated post-LT patients underwent liver biopsy prior to therapy, and 52.2% had at least F1 METAVIR fibrosis. 87.5% (N=14/16) of active waitlist patients received DAA and achieved SVR. HCV eradication did not result in higher rates of delisting for HCC progression. Due to local HCC listing criteria of total tumor volume and AFP, 60% (N=18/30) of HCV+/HCC patients were beyond Milan criteria at the time of LT. Despite this, there was no difference in HCC recurrence rates post-LT, whether patients achieved SVR pre- or post-LT.
Conclusions: These data suggest that HCV eradication pre-LT does not significantly impact waitlist time for HCV+ patients with HCC. HCV eradication does not impact rates of delisting for HCC progression or rates of HCC recurrence post-LT.

BACKGROUND: Cognitive impairment is commonly reported in patients receiving chemotherapy, but the acuity of onset is not known. This study utilized the psychomotor vigilance test (PVT) and trail-making test B (TMT-B) to assess cognitive impairment immediately post-chemotherapy.
METHODS: Patients aged 18-80 years receiving first-line intravenous chemotherapy for any stage of breast or colorectal cancer were eligible. Patient symptoms, peripheral neuropathy and Stanford Sleepiness Scale were assessed. A five-minute PVT and TMT-B were completed on a tablet computer pre-chemotherapy and immediately post-chemotherapy. Using a mixed linear regression model, changes in reciprocal transformed PVT reaction time (mean 1/RT) were assessed. A priori, an increase in median PVT reaction times by > 20 ms (approximating PVT changes with blood alcohol concentrations of 0.04-0.05 g%) was considered clinically relevant.
RESULTS: One hundred forty-two cancer patients (73 breast, 69 colorectal, median age 55.5 years) were tested. Post-chemotherapy, mean 1/RT values were significantly slowed compared to pre-chemotherapy baseline (p = 0.01). This corresponded to a median PVT reaction time slowed by an average of 12.4 ms. Changes in PVT reaction times were not correlated with age, sex, cancer type, treatment setting, or use of supportive medications. Median post-chemotherapy PVT reaction time slowed by an average of 22.5 ms in breast cancer patients and by 1.6 ms in colorectal cancer patients. Post-chemotherapy median PVT times slowed by > 20 ms in 57 patients (40.1%). Exploratory analyses found no statistically significant association between the primary outcome and self-reported anxiety, fatigue or depression. TMT-B completion speed improved significantly post-chemotherapy (p = 0.03), likely due to test-retest phenomenon.
CONCLUSIONS: PVT reaction time slowed significantly immediately post-chemotherapy compared to a pre-chemotherapy baseline, and levels of impairment similar to effects of alcohol consumption in other studies was seen in 40% of patients. Further studies assessing functional impact of cognitive impairment on patients immediately after chemotherapy are warranted.