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Aim: To determine the knowledge of certain University of Nigeria Teaching Hospital, (UNTH) staff about ARI case management and the impact of ARI case management training on their knowledge. Materials and Methods: This was done during two three-day training courses, which were based on the National Acute Respiratory Infections Programme (NARIP) adaptation of the WHO standard case management module. Pre- and post- (training) tests were done and were marked by the same person. Results: The general mean±S.D pre- and post-test scores were 38.68± 10.22% and 73.44±18.35% respectively (P

Background: Surgery improves long-term survival for resectable, liver-only metastatic colorectal cancer (mCRC). With no consensus definition of "resectable" disease, decisions regarding resectability are reliant on the expertise and judgement of the treating clinician working in consultation with a multidisciplinary team (MDT). This study examines the clinical outcome versus initial assessment of resectability in an Australian population with mCRC., Patients and Methods: Patients with liver-only mCRC diagnosed January 2009 to December 2022 were identified from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry. Patients were classified based on prospectively documented treatment assessment as "resectable," "potentially resectable," or "unresectable." The correlation between initial assessment of resectability and clinical outcome, and any impact of clinicopathologic factors were examined. Kaplan-Meier analysis assessed overall survival based on initial resectability assessment and resection status., Results: Of 4437 patients with mCRC identified through TRACC, 1250 (28%) had liver-only disease at presentation, with 497 (43%), 277 (24%), and 374 (33%) classified as "unresectable," "potentially resectable," and "resectable," respectively. In total, 516 (41%) ultimately underwent surgical resection, including 30 (6%) of the "initially unresectable," 148 (53%) of the "potentially resectable," and 338 (90%) of the "resectable" at a median of 9.5, 5.9, and 2.4 months from the diagnosis of liver metastases, respectively. Resection in the "unresectable" patient population was associated with younger age (mean age 63 vs. 69, P = .0006), better performance status (ECOG 0-1 100% vs. 74%, P = .0017), and fewer comorbidities (Charlson index 0-3 in 73% vs. 53%, P = .0296) compared with no resection. Median overall survival was longer for resected versus nonresected patients across all categories: "unresectable" (59.2 vs. 17.6 months, P < .0001), "potentially resectable" (57.2 vs. 22.8 months, P < .0001), and "resectable" (108 vs. 55 months, P < .0001)., Conclusions: This real-world study demonstrates the potential for "initially unresectable" patients to become surgical candidates following systemic therapy, more likely in younger and fitter patients, with overall excellent survival outcomes in resected patients. This highlights the value of routine, repeated MDT assessments for patients with liver-only disease who are continuing to respond to systemic therapy, even for those initially considered never to be surgical candidates., Competing Interests: Disclosure None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Accurately capturing children's word learning abilities is critical for advancing our understanding of language development. Researchers have demonstrated that utilizing more complex statistical methods, such as mixed-effects regression and hierarchical linear modeling, can lead to a more complete understanding of the variability observed within children's word learning abilities. In the current paper, we demonstrate how a person-centered approach to data analysis can provide additional insights into the heterogeneity of word learning ability among children while also aiding researchers' efforts to draw individual-level conclusions. Using previously published data with 32 typically developing and 32 late-talking infants who completed a novel noun generalization (NNG) task to assess word learning biases (i.e., shape and material biases), we compare this person-centered method to three traditional statistical approaches: (1) a t -test against chance, (2) an analysis of variance (ANOVA), and (3) a mixed-effects regression. With each comparison, we present a novel question raised by the person-centered approach and show how results from the corresponding analyses can lead to greater nuance in our understanding of children's word learning capabilities. Person-centered methods, then, are shown to be valuable tools that should be added to the growing body of sophisticated statistical procedures used by modern researchers.

The cap-pushing response (CPR) is a new free-flying technique used to study learning and memory in honey bees. Bees fly to a target where they push a cap to reveal a hidden food source. When combined with traditional odor and color targets, the CPR technique opens the door to additional choice preference tests in honey bees. To facilitate the use of the CPR technique, three experiments were conducted. Experiment 1 investigates the impact of extended training on the CPR response and its role in extinction. Experiment 2 explores the role of CPR in overshadowing, and Experiment 3 explores the effects of electric shock punishment on the CPR technique. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background & Aims: Dysbiosis of gut microbiota is linked to the development of colorectal cancer (CRC). However, microbiota-based stratification of CRC tissue and how this relates to clinicomolecular characteristics and prognosis remains to be clarified., Methods: Tumor and normal mucosa from 423 patients with stage I to IV CRC were profiled by bacterial 16S rRNA gene sequencing. Tumors were characterized for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), APC, BRAF, KRAS, PIK3CA, FBXW7, SMAD4, and TP53 mutations, subsets for chromosome instability (CIN), mutation signatures, and consensus molecular subtypes (CMS). Microbial clusters were validated in an independent cohort of 293 stage II/III tumors., Results: Tumors reproducibly stratified into 3 oncomicrobial community subtypes (OCSs) with distinguishing features: OCS1 (Fusobacterium/oral pathogens, proteolytic, 21%), right-sided, high-grade, MSI-high, CIMP-positive, CMS1, BRAF V600E, and FBXW7 mutated; OCS2 (Firmicutes/Bacteroidetes, saccharolytic, 44%), and OCS3 (Escherichia/Pseudescherichia/Shigella, fatty acid β-oxidation, 35%) both left-sided and exhibiting CIN. OCS1 was associated with MSI-related mutation signatures (SBS15, SBS20, ID2, and ID7) and OCS2 and OCS3 with SBS18 related to damage by reactive oxygen species. Among stage II/III patients, OCS1 and OCS3 both had poorer overall survival compared with OCS2 for microsatellite stable tumors (multivariate hazard ratio [HR], 1.85; 95% confidence interval [CI], 1.15-2.99; P = .012; and HR, 1.52; 95% CI 1.01-2.29; P = .044, respectively) and left-sided tumors (multivariate HR, 2.66; 95% CI, 1.45-4.86; P = .002; and HR, 1.76; 95% CI, 1.03-3.02; P = .039, respectively)., Conclusions: OCS classification stratified CRCs into 3 distinct subgroups with different clinicomolecular features and outcomes. Our findings provide a framework for a microbiota-based stratification of CRC to refine prognostication and to inform the development of microbiota-targeted interventions., (Copyright © 2023 AGA Institute. All rights reserved.)

Background: This retrospective cohort study reports on overall survival and short-term complications, comparing laparoscopic to open resection for right-sided colon cancers. It is one of the largest studies in the field with generalizable population-level results., Method: This study on right sided colon cancers used prospectively collected administrative data linked to a death registry over 5 years from 2014 to 2018. Exclusion criteria were private patients, patients aged less than 10 years, synchronous and metachronous cancers. Propensity score weighting was used to balance cohorts and Cox proportional hazards regression was used to assess the hazard of death. In addition, logistic regression analysis was used to assess secondary outcomes. For completeness, unweighted data was similarly analysed., Results: There were 3603 patients identified for the analysis: 1729 open patients and 1874 laparoscopic patients. Cox proportional hazards regression analysis of the weighted data showed no evidence of a statistically significant effect of laparoscopic surgery compared to open surgery on overall survival for right-sided colon cancers (HR 0.86, 95% CI 0.71-1.04, P = 0.112). The weighted data showed lower odds of prolonged length of stay, return to theatre and discharge destination other than home in the laparoscopic cohort compared to the open cohort. There was no difference in inpatient mortality. Unweighted results were similar., Conclusion: This study validates the use of laparoscopic surgery for right-sided colon cancer, showing similar long-term overall survival and inpatient mortality compared to open surgery. It is superior to open surgery for the short-term outcomes of LOS, return to theatre and discharge destination other than home., (© 2023 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Coral reef soundscapes are increasingly studied for their ecological uses by invertebrates and fishes, for monitoring habitat quality, and to investigate effects of anthropogenic noise pollution. Few examinations of aquatic soundscapes have reported particle motion levels and variability, despite their relevance to invertebrates and fishes. In this study, ambient particle acceleration was quantified from orthogonal hydrophone arrays over several months at four coral reef sites, which varied in benthic habitat and fish communities. Time-averaged particle acceleration magnitudes were similar across axes, within 3 dB. Temporal trends of particle acceleration corresponded with those of sound pressure, and the strength of diel trends in both metrics significantly correlated with percent coral cover. Higher magnitude particle accelerations diverged further from pressure values, potentially representing sounds recorded in the near field. Particle acceleration levels were also reported for boat and example fish sounds. Comparisons with particle acceleration derived audiograms suggest the greatest capacity of invertebrates and fishes to detect soundscape components below 100 Hz, and poorer detectability of soundscapes by invertebrates compared to fishes. Based on these results, research foci are discussed for which reporting of particle motion is essential, versus those for which sound pressure may suffice.

Aim: A diverting ileostomy is typically performed to divert intestinal contents in high-risk colorectal anastomoses. Ileostomy closure is associated with high rates of postoperative Clostridium difficile infection (CDI). Risk factors for the development of CDI are unclear; however, a correlation has been observed with delayed closure. This study aimed to assess the odds of developing CDI in patients who had a delay to reversal of ileostomy, compared to those who had no delay., Methods: A retrospective cohort study was conducted of patients undergoing reversal of ileostomy between 2010 and 2019 at a single tertiary centre. A delay to reversal of ileostomy was defined if the procedure was performed at >365 days following the index procedure. CDI was defined as the presence of Clostridium difficile toxin associated with diarrhoea. Univariable logistic regression analysis was performed to estimate odds of CDI for each covariable, comparing patients who had a delay to reversal of ileostomy with those who did not. Multivariable logistic regression analysis was used to adjust for the potential confounding effects of covariables., Results: Of 195 patients, 11 (5.6%), developed postoperative CDI. Multivariable analysis showed that delay to reversal of ileostomy was associated with a nearly 7-fold increase in odds of CDI (OR = 6.95, CI: 1.06-81.6; p-value = 0.03)., Conclusion: A delay to reversal of ileostomy of >365 days was associated with a higher incidence of CDI postoperatively. Careful consideration should be given to the timing of reversal and appropriate preoperative counselling of patients., (© 2021 The Association of Coloproctology of Great Britain and Ireland.)

Harmful algal blooms produce potent neurotoxins that accumulate in seafood and are hazardous to human health. Developmental exposure to the harmful algal bloom toxin, domoic acid (DomA), has behavioral consequences well into adulthood, but the cellular and molecular mechanisms of DomA developmental neurotoxicity are largely unknown. To assess these, we exposed zebrafish embryos to DomA during the previously identified window of susceptibility and used the well-known startle response circuit as a tool to identify specific neuronal components that are targeted by exposure to DomA. Exposure to DomA reduced startle responsiveness to both auditory/vibrational and electrical stimuli, and even at the highest stimulus intensities tested, led to a dramatic reduction of one type of startle (short-latency c-starts). Furthermore, DomA-exposed larvae had altered kinematics for both types of startle responses tested, exhibiting shallower bend angles and slower maximal angular velocities. Using vital dye staining, immunolabeling, and live imaging of transgenic lines, we determined that although the sensory inputs were intact, the reticulospinal neurons required for short-latency c-starts were absent in most DomA-exposed larvae. Furthermore, axon tracing revealed that DomA-treated larvae also showed significantly reduced primary motor neuron axon collaterals. Overall, these results show that developmental exposure to DomA targets large reticulospinal neurons and motor neuron axon collaterals, resulting in measurable deficits in startle behavior. They further provide a framework for using the startle response circuit to identify specific neural populations disrupted by toxins or toxicants and to link these disruptions to functional consequences for neural circuit function and behavior., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Neoadjuvant chemoradiation therapy is standard-of-care treatment for locally advanced rectal cancer (LARC). A pathological complete response (pCR) following chemoradiation therapy is an early indicator of treatment benefit and associated with excellent survival outcomes, with capecitabine largely replacing infusional 5-fluorouracil as the choice in routine care of LARC., Aims: To analyse the uptake of capecitabine usage over time, and on the back of clinical trial data demonstrating equivalence between fluoropyrimidines, confirm that efficacy is maintained in the real-world setting., Methods: We analysed data from a prospectively maintained colorectal cancer database at three Australian hospitals including patients diagnosed from January 2009 to December 2018. Pathological response was determined as either complete or incomplete and compared for patients receiving 5-FU or capecitabine., Results: A total of 657 patients was analysed, 498 receiving infusional 5-FU and 159 capecitabine. Capecitabine use has markedly increased from approval in 2014 in Australia, now being used in more than 80% of patients. Patient characteristics were similar by treatment, including age, tumour location and pre-treatment stage. pCR was reported in 22/159 (13.8%) of capecitabine-treated patients and 118/380 (23.7%) that received 5-FU (P ≤ 0.01). More capecitabine-treated patients received post-operative oxaliplatin (44.2% vs 6.3%, P < 0.01). Two-year progression-free survival was similar (84.9% vs 88.0%, P = 0.34)., Conclusions: Capecitabine is now the dominantly used neoadjuvant chemotherapy in LARC. Capecitabine use was associated with a lower rate of pCR versus infusional 5-FU, a difference not explained by examined patient or tumour characteristics. Poor treatment compliance with oral therapy in the real-world setting is one possible explanation., (© 2020 Royal Australasian College of Physicians.)

Although many crustaceans produce sounds, their hearing abilities and mechanisms are poorly understood, leaving uncertainties regarding whether or how these animals use sound for acoustic communication. Marine invertebrates lack gas-filled organs required for sound pressure detection, but some of them are known to be sensitive to particle motion. Here, we examined whether the American lobster ( Homarus americanus ) could detect sound and subsequently sought to discern the auditory mechanisms. Acoustic stimuli responses were measured using auditory evoked potential (AEP) methods. Neurophysiological responses were obtained from the brain using tone pips between 80 and 250 Hz, with best sensitivity at 80-120 Hz. There were no significant differences between the auditory thresholds of males and females. Repeated controls (recordings from deceased lobsters, moving electrodes away from the brain and reducing seawater temperature) indicated the evoked potentials' neuronal origin. In addition, AEP responses were similar before and after antennules (including statocysts) were ablated, demonstrating that the statocysts, a long-proposed auditory structure in crustaceans, are not the sensory organs responsible for lobster sound detection. However, AEPs could be eliminated (or highly reduced) after immobilizing hairfans, which cover much of lobster bodies. These results suggest that these external cuticular hairs are likely to be responsible for sound detection, and imply that hearing is mechanistically possible in a wider array of invertebrates than previously considered. Because the lobsters' hearing range encompasses the fundamental frequency of their buzzing sounds, it is likely that they use sound for intraspecific communication, broadening our understanding of the sensory ecology of this commercially vital species. The lobsters' low-frequency acoustic sensitivity also underscores clear concerns about the potential impacts of anthropogenic noise., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Anthropogenic noise can cause diverse changes in animals' behaviors, but effects on feeding behaviors are understudied, especially for key invertebrate taxa. With the offshore wind industry expanding, concern exists regarding potential impacts of pile driving noise on squid and other commercially and ecologically vital taxa. We investigated changes in feeding and alarm (defense) behaviors of squid, Doryteuthis pealeii, predating on killifish, Fundulus heteroclitus, during playbacks of pile driving noise recorded from wind farm construction within squids' habitat. Fewer squid captured killifish during noise exposure compared to controls. Squid had more failed predation attempts when noise was started during predation sequences. Alarm responses to noise were similar whether or not squid were hunting killifish, indicating similar vigilance to threat stimuli in these contexts. Additionally, novel hearing measurements on F. heteroclitus confirmed they could detect the noise. These results indicate noise can disrupt feeding behaviors of a key invertebrate species, and will leverage future studies on how noise may disrupt squids' vital ecological interactions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

TP53 mutations drive colorectal cancer development, with missense mutations frequently leading to accumulation of abnormal TP53 protein. TP53 alterations have been associated with poor prognosis and chemotherapy resistance, but data remain controversial. Here, we examined the predictive utility of TP53 overexpression in the context of current adjuvant treatment practice for patients with stage III colorectal cancer. A prospective cohort of 264 stage III patients was tested for association of TP53 expression with 5-year disease-free survival, grouped by adjuvant treatment. Findings were validated in an independent retrospective cohort of 274 stage III patients. Overexpression of TP53 protein (TP53+) was found in 53% and 52% of cases from the prospective and retrospective cohorts, respectively. Among patients receiving adjuvant chemotherapy, TP53+ status was associated with shorter disease-free survival (p ≤ 0.026 for both cohorts), while no difference in outcomes between TP53+ and TP53- cases was observed for patients treated with surgery alone. Considering patients with TP53- tumors, those receiving adjuvant treatment had better outcomes compared with those treated with surgery alone (p ≤ 0.018 for both cohorts), while no treatment benefit was apparent for patients with TP53+ tumors. Combined cohort-stratified analysis adjusted for clinicopathological variables and DNA mismatch repair status confirmed a significant interaction between TP53 expression and adjuvant treatment for disease-free survival (p interaction  = 0.030). For the combined cohort, the multivariate hazard ratio for TP53 overexpression among patients receiving adjuvant chemotherapy was 2.03 (95% confidence interval 1.41-2.95, p < 0.001), while the hazard ratio for adjuvant treatment among patients with TP53- tumors was 0.42 (95% confidence interval 0.24-0.71, p = 0.001). Findings were maintained irrespective of tumor location or when restricted to mismatch repair-proficient tumors. Our data suggest that adjuvant chemotherapy benefit in stage III colorectal cancer is restricted to cases with low-level TP53 protein expression. Identifying TP53+ tumors could highlight patients that may benefit from more aggressive treatment or follow-up.

Pile driving occurs during construction of marine platforms, including offshore windfarms, producing intense sounds that can adversely affect marine animals. We quantified how a commercially and economically important squid (Doryteuthis pealeii: Lesueur 1821) responded to pile driving sounds recorded from a windfarm installation within this species' habitat. Fifteen-minute portions of these sounds were played to 16 individual squid. A subset of animals (n = 11) received a second exposure after a 24-h rest period. Body pattern changes, inking, jetting, and startle responses were observed and nearly all squid exhibited at least one response. These responses occurred primarily during the first 8 impulses and diminished quickly, indicating potential rapid, short-term habituation. Similar response rates were seen 24-h later, suggesting squid re-sensitized to the noise. Increased tolerance of anti-predatory alarm responses may alter squids' ability to deter and evade predators. Noise exposure may also disrupt normal intraspecific communication and ecologically relevant responses to sound., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Importance: Adjuvant chemotherapy in patients with stage III colon cancer prevents recurrence by eradicating minimal residual disease. However, which patients remain at high risk of recurrence after completing standard adjuvant treatment cannot currently be determined. Postsurgical circulating tumor DNA (ctDNA) analysis can detect minimal residual disease and is associated with recurrence in colorectal cancers., Objective: To determine whether serial postsurgical and postchemotherapy ctDNA analysis could provide a real-time indication of adjuvant therapy efficacy in stage III colon cancer., Design, Setting, and Participants: This multicenter, Australian, population-based cohort biomarker study recruited 100 consecutive patients with newly diagnosed stage III colon cancer planned for 24 weeks of adjuvant chemotherapy from November 1, 2014, through May 31, 2017. Patients with another malignant neoplasm diagnosed within the last 3 years were excluded. Median duration of follow-up was 28.9 months (range, 11.6-46.4 months). Physicians were blinded to ctDNA results. Data were analyzed from December 10, 2018, through June 23, 2019., Exposures: Serial plasma samples were collected after surgery and after chemotherapy. Somatic mutations in individual patients' tumors were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. Personalized assays were designed to quantify ctDNA., Main Outcomes and Measures: Detection of ctDNA and recurrence-free interval (RFI)., Results: After 4 exclusions, 96 eligible patients were eligible; median patient age was 64 years (range, 26-82 years); 49 (51%) were men. At least 1 somatic mutation was identified in the tumor tissue of all 96 evaluable patients. Circulating tumor DNA was detectable in 20 of 96 (21%) postsurgical samples and was associated with inferior recurrence-free survival (hazard ratio [HR], 3.8; 95% CI, 2.4-21.0; P < .001). Circulating tumor DNA was detectable in 15 of 88 (17%) postchemotherapy samples. The estimated 3-year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR, 6.8; 95% CI, 11.0-157.0; P < .001). Postsurgical ctDNA status remained independently associated with RFI after adjusting for known clinicopathologic risk factors (HR, 7.5; 95% CI, 3.5-16.1; P < .001)., Conclusions and Relevance: Results suggest that ctDNA analysis after surgery is a promising prognostic marker in stage III colon cancer. Postchemotherapy ctDNA analysis may define a patient subset that remains at high risk of recurrence despite completing standard adjuvant treatment. This high-risk population presents a unique opportunity to explore additional therapeutic approaches.

Adjuvant! Online Inc (A!O), the Memorial Sloan Kettering Cancer Center (MSKCC), MD Anderson (MDA) and Mayo Clinic (MC) provide calculators to predict survival probabilities for patients with resected early-stage colon cancer, trained on data from United States (US) patient cohorts or patients enrolled in international clinical trials. Limited data exist on the transferability of calculators across healthcare systems. Calculator transferability to Australian community practice was evaluated for 1,401 stage II/III patients. Calibration and discrimination were assessed for overall (OS), cancer-specific (CSS) or recurrence-free survival (RFS). The US patient cohort-based calculators, A!O, MSKCC and MDA, significantly overestimated risks of recurrence and death in Australian patients, with 5-year OS, CSS and RFS prediction differences of -6.5% to -9.9%, -9.1% to -14.4% and - 3.8% to -6.8%, respectively (p < 0.001). Significant heterogeneity in calibration was observed for subgroups by tumor stage and treatment, age, gender, tumor location, ECOG and ASA score. Calibration appeared acceptable for the clinical trial patient-based MC calculator, but restricted tool applicability (stage III patients, ≥12 examined lymph nodes, receiving adjuvant treatment) limited the sample size. Compared to AJCC 7th edition tumor staging, calculators showed improved discrimination for OS, but no improvement for CSS and RFS. In conclusion, deficiencies in calibration limited transferability of US patient cohort-based survival calculators for early-stage colon cancer to the setting of Australian community practice. Our results demonstrate the utility for multi-feature survival calculators to improve OS predictions but highlight the importance for performance assessment of tools prior to implementation in an external health care setting., (© 2019 UICC.)

Objective: For patients with locally advanced rectal cancer (LARC), adjuvant chemotherapy selection following surgery remains a major clinical dilemma. Here, we investigated the ability of circulating tumour DNA (ctDNA) to improve risk stratification in patients with LARC., Design: We enrolled patients with LARC (T3/T4 and/or N+) planned for neoadjuvant chemoradiotherapy. Plasma samples were collected pretreatment, postchemoradiotherapy and 4-10 weeks after surgery. Somatic mutations in individual patient's tumour were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. We then designed personalised assays to quantify ctDNA in plasma samples. Patients received adjuvant therapy at clinician discretion, blinded to the ctDNA results., Results: We analysed 462 serial plasma samples from 159 patients. ctDNA was detectable in 77%, 8.3% and 12% of pretreatment, postchemoradiotherapy and postsurgery plasma samples. Significantly worse recurrence-free survival was seen if ctDNA was detectable after chemoradiotherapy (HR 6.6; P<0.001) or after surgery (HR 13.0; P<0.001). The estimated 3-year recurrence-free survival was 33% for the postoperative ctDNA-positive patients and 87% for the postoperative ctDNA-negative patients. Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (chemotherapy: HR 10.0; P<0.001; without chemotherapy: HR 22.0; P<0.001). Postoperative ctDNA status remained an independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors (HR 6.0; P<0.001)., Conclusion: Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy., Competing Interests: Competing interests: KK, NP, LD and BV are founders of PapGene and Personal Genome Diagnostics and members of the Scientific Advisory Boards of Morphotek and Sysmex-Inostics. IK is an employee of PapGene. These companies and others have licensed patent applications on genetic technologies from Johns Hopkins, some of which result in royalty payments to KK, NP, LD, BV, and IK. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear., Design: A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF / KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients., Results: Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; P multivariate <0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; P multivariate =0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/ BRAF wt / KRAS wt , pMMR/ BRAF mut / KRAS wt , pMMR/ BRAF wt / KRAS mut ) and transcriptomic (CMS 1-4) subtypes., Conclusion: TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Over the past decade, 2 major modalities for noninvasive skin tightening have emerged: monopolar capacitive-coupled radiofrequency (MRF) and microfocused ultrasound with visualization (MFU-V). Up to date, no comparative clinical trials have been performed., Objective: To compare the efficacy and safety of MRF versus MFU-V for the lifting and tightening of the face and neck., Materials and Methods: Twenty subjects with mild to moderate skin laxity received MFU-V over one-side of the face and MRF over the other side of the face at the same time. Subjects were followed for 6 months., Results: Both MRF and MFU-V led to a decrease in the Fasil Face and Neck Laxity Grading Scale (FLR). These differences became significant at Day 30 and remained significantly improved through Days 90 and 180 in both groups. There was no statistically significant difference in the FLR Scale between MRF-treated and MFU-V-treated sides. Subjects' Global Aesthetic Improvement Scale showed improvement at Day 30, 90, and 180., Conclusion: Both MRF and MFU-V led to significant improvement in face and neck laxity. There were no statistical differences between MRF and MFU-V in standardized investigator measures of face and neck laxity, patient satisfaction, and adverse events.

Background: The nonablative, fractional, 1,927-nm diode laser is theoretically a safe and effective treatment for hyperpigmentation and melasma in darker skin and may potentiate topical cosmeceutical delivery., Objective: To evaluate the use of a nonablative, fractional, 1,927-nm diode laser with and without topical 2% hydroquinone (HQ) cream for moderate-to-severe facial hyperpigmentation in Fitzpatrick skin Types III-V., Methods: Forty adults underwent 4 laser treatments at 2-week intervals and were randomized to daily application of 2% HQ cream or moisturizer. Follow-ups were conducted 4 and 12 weeks after the final laser treatment., Results: Hydroquinone and moisturizer groups demonstrated Mottled Pigmentation Area and Severity Index improvements of approximately 50% at post-treatment Weeks 4 and 12. Blinded investigator-assessed hyperpigmentation and photodamage improved significantly for both the groups at post-treatment Weeks 4 and 12. Subject satisfaction improved significantly in both the groups by post-treatment Week 4. Although investigator-rated Global Aesthetic Improvement Scale scores were significantly better in the HQ group at post-treatment Week 12, satisfaction was higher among those using moisturizer. No adverse events were noted., Conclusion: The nonablative, fractional, 1,927-nm diode laser produced significant improvement in hyperpigmentation in Fitzpatrick skin Types III-V by 4 weeks, with maintenance of results at 12 weeks after treatment even without HQ.

Background: Few effective treatments exist for striae alba, which are the mature stage of stretch marks., Objective: To evaluate the efficacy of the nonablative fractional 1,565-nm Erbium-glass (Er:glass) and the picosecond fractional 1,064/532-nm neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers in the treatment of striae alba., Materials and Methods: Twenty subjects with striae alba on the bilateral abdomen were treated with either the nonablative fractional 1565-nm Er:glass or the picosecond fractional 1,064/532-nm Nd:YAG laser, with a total of 3 treatments 3 weeks apart., Results: A 31% (1.25/4) texture improvement was noted for both the fractional 1,565-nm Er:glass laser and the picosecond fractional 1,064/532-nm Nd:YAG laser. The degree of atrophy was improved by 30% (1.19/4) with the 1,565-nm Er:glass laser and 35% (1.38/4) with the picosecond 1,064/532-nm Nd:YAG laser. A 48% (1.9/4) subject overall assessment of improvement was noted with the fractional 1565-nm Er:glass laser and 45% (1.8/4) improvement with the picosecond fractional 1,064/532-nm Nd:YAG laser. There was no significant change in striae density with either laser. The picosecond laser was rated as less painful during all 3 sessions (p = .002) and had a shorter healing time (p = .035). The nonablative fractional 1,565-nm Er:glass and the picosecond fractional 1,064/532-nm Nd:YAG lasers were equally efficacious in improving striae alba.

Background: Multiple studies have defined the prognostic and potential predictive significance of the primary tumor side in metastatic colorectal cancer (CRC). However, the currently available data for early-stage disease are limited and inconsistent., Materials and Methods: We explored the clinicopathologic, treatment, and outcome data from a multisite Australian CRC registry from 2003 to 2016. Tumors at and distal to the splenic flexure were considered a left primary (LP)., Results: For the 6547 patients identified, the median age at diagnosis was 69 years, 55% were men, and most (63%) had a LP. Comparing the outcomes for right primary (RP) versus LP, time-to-recurrence was similar for stage I and III disease, but longer for those with a stage II RP (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.52-0.90; P < .01). Adjuvant chemotherapy provided a consistent benefit in stage III disease, regardless of the tumor side. Overall survival (OS) was similar for those with stage I and II disease between LP and RP patients; however, those with stage III RP disease had poorer OS (HR, 1.30; 95% CI, 1.04-1.62; P < .05) and cancer-specific survival (HR, 1.55; 95% CI, 1.19-2.03; P < .01). Patients with stage IV RP, whether de novo metastatic (HR, 1.15; 95% CI, 0.95-1.39) or relapsed post-early-stage disease (HR, 1.35; 95% CI, 1.11-1.65; P < .01), had poorer OS., Conclusion: In early-stage CRC, the association of tumor side and effect on the time-to-recurrence and OS varies by stage. In stage III patients with an RP, poorer OS and cancer-specific survival outcomes are, in part, driven by inferior survival after recurrence, and tumor side did not influence adjuvant chemotherapy benefit., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Background: The chin is a critical component to the perception of facial attractiveness. Dermal fillers offer a nonsurgical, temporary method of correcting mild to moderate chin retrusion and resorption. Thus far, discussion of this procedure has been largely limited to the plastic surgery and otolaryngology literature., Objective: To review pertinent aspects of anatomy, patient evaluation, injection technique, concomitant therapies, and complications in chin augmentation using injectable fillers., Methods: A brief review of the literature surrounding chin augmentation using injectable fillers, as well as the authors' experience in this area, is provided., Results: Chin augmentation using injectable fillers can be performed effectively and safely with adequate background knowledge of the regional anatomy and appropriate patient selection. The authors discuss both injection techniques in the published literature and their own approach. Potential complications and concomitant therapies are also reviewed., Conclusion: As chin augmentation is increasingly recognized as an essential component to complete facial aesthetic rejuvenation, dermatologic surgeons should be familiar with how to safely and effectively perform augmentation with injectable fillers to achieve an optimal cosmetic outcome.

Background: The visible signs of photodamage can be improved by intense pulsed light (IPL). Active ingredients in cosmeceuticals also have effects on skin quality and pigmentation, and can camouflage post-treatment side effects. Combination therapies utilizing different treatment modalities have been shown to optimize clinical outcomes for skin rejuvenation and patient satisfaction., Aim: To evaluate the efficacy of a combination of IPL with a daily topical skincare and sunscreen regimen for the treatment of facial photodamage and for the improvement of IPL treatment tolerability., Patients/methods: Twenty female subjects with moderate-to-severe facial photodamage, with past history of IPL treatments, received one IPL treatment followed by the use of the topical skincare regimen for 8 weeks. An investigator assessed facial photodamage and hyperpigmentation at baseline, week 4, and week 8, and postprocedure erythema. Subject questionnaires were also administered at each visit., Results: Compared to baseline, there was a significant improvement in photodamage and hyperpigmentation of bare facial skin. The application of the skincare regimen resulted in a significant reduction in post-IPL erythema, stinging/burning, and itching. The majority of patients were very satisfied or satisfied and felt the treatment regimen improved various aspects of skin quality and the tolerability of the procedure., Conclusions: The addition of a topical skincare regimen after IPL treatment to the face resulted in significant improvements in facial photodamage and pigmentation, decreased post-treatment side effects, and increased tolerability., (© 2017 Wiley Periodicals, Inc.)

Background: "Skin boosting" with injections of hyaluronic acid has been demonstrated to improve aged skin., Objective: The aim of this study was to determine the efficacy and safety of small-particle hyaluronic acid with lidocaine (SP-HAL) microaliquots for the correction of fine lines of the cheeks., Materials and Methods: Twenty subjects with mild to moderate static mid to lower cheek rhytides were enrolled. The right or left cheek was randomized to receive 1 mL of SP-HAL using a microdroplet technique, with the contralateral cheek treated with sham injection of sterile normal saline. The degree of cheek wrinkling and elastosis based on the Fitzpatrick-Goldman Wrinkle and Elastosis Scale was assessed at baseline and 7, 14, 30, 90, and 180 days after treatment. Subjects rated their satisfaction at days 90 and 180., Results: Fourteen patients completed the study. There were no statistically significant improvements in wrinkling or elastosis of the SP-HAL-treated cheek or control cheek at any time point. In addition, there were no significant differences in wrinkling, elastosis, or patient satisfaction between the treatment cheek and control cheek., Conclusion: One treatment of intradermal microdroplet injections of SP-HAL to the mid to lower cheek failed to show superiority over normal saline in improving clinical signs of skin wrinkling and elastosis.

Background: Although transcutaneous temperature-controlled radiofrequency (TTCRF) may effectively treat vulvovaginal laxity (VVL), atrophic vaginitis (AV), orgasmic dysfunction (OD), and stress urinary incontinence (SUI), there is a lack of histopathologic evidence to validate its use., Objective: Evaluate clinical and histological changes induced by vulvovaginal TTCRF., Materials and Methods: This was a prospective, nonrandomized trial. Ten female subjects with mild-to-moderate VVL, with or without AV, OD, and/or SUI underwent 3 TTCRFs at 4-week intervals. Five subjects underwent pre- and post-treatment biopsies of the labia majora and vaginal canal for histology. Assessments were performed at baseline and Days 10, 30, 60, and 120., Results: Investigator-rated VVL improved significantly from baseline to Day 10, with improvement maintained through Day 120 (p = .001 and .001, respectively). Sexual satisfaction improved significantly by Day 60 (p = .001). Improvement in AV reached significance at Day 120 (p = .048). Although OD and SUI improved steadily, the difference in improvement did not reach statistical significance. Histology revealed that post-treatment increases in collagen, elastin, vascularity, and small nerve fibers., Conclusion: Transcutaneous temperature-controlled RF resulted in significant improvements in AV, VVL, and sexual satisfaction with milder improvements in OD and SUI. Post-treatment histology demonstrated neocollagenesis, neoelastogenesis, neoangiogenesis, and the first reported finding of TTCRF-related neurogenesis.

Background: Cryolipolysis is a non-invasive method of body shaping that has been used for male pseudogynecomastia. However, traditional vacuum suction cryolipolysis requires a minimum pinchable fat layer which may not always be present in this area., Objective: To evaluate the efficacy and safety of a conformable surface cryolipolysis applicator for the reduction of male pseudogynecomastia., Materials and Methods: Ten male subjects with pseudogynecomastia received two cycles of cryolipolysis to the breast 6 weeks apart. Ultrasound was used to measure the thickness of adipose tissue., Results: Seven of 10 patients completed the study. Compared to baseline, the mean ± SD change in adipose tissue thickness was 8.12 ± 6.94 mm for the treated versus 1.03 ± 6.03 mm for the control breast at week 6 (p = 0.014), and 8.71 ± 7.04 mm for the treated vs. 2.66 ± 7.04 mm for the control breast at week 12 (P = 0.16). Four (4) of seven (57%) patients were at least slightly satisfied with the treated breast, and although subject satisfaction was higher in the treated breast, this did not reach significance (0.085). Adverse events were mild and transient., Conclusion: A conformable surface cryolipolysis applicator was effective in reducing the mean adipose tissue thickness in subjects with male pseudogynecomastia. Lasers Surg. Med. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

Injection of neurotoxin is the most commonly performed cosmetic procedure in the United States, and the total number of male patients seeking botulinum has steadily increased over the years. Because of their unique aesthetic goals, expectations, and anatomy, men require differing botulinum toxin doses and techniques. This article provides an evidence-based approach to botulinum toxin in men. Each area of the face is discussed separately, focusing on gender differences in anatomy, treatment goals, and injection method., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Infraorbital dark circles result from a combination of factors. The fractionated picosecond 755 nm alexandrite laser and dual wavelength picosecond Nd:YAG laser have not been examined as a method of addressing infraorbital hyperpigmentation., Objective: To determine the efficacy and safety of treatment of infraorbital dark circles using fractionated picosecond 755 nm and dual wavelength picosecond Nd:YAG laser., Methods and Materials: These trials did not utilize a comparative design; rather, these were separate, prospective, open-label, evaluator-blinded trials utilizing two treatment regimens: (i) 19 adult subjects were treated in a single session with the dual wavelengths of 532 nm and 1,064 nm in consecutive passes using the fractionated lens; (ii) 10 adult subjects were treated using the picosecond 755 nm laser via the fractionated lens in three treatment sessions at 3 week intervals. Subjects in both studies were followed-up for blinded-investigator assessment of infraorbital hyperpigmentation, adverse events, and improvement compared to baseline., Results: The dual wavelength picosecond Nd:YAG laser, blinded-investigator assessment did not demonstrate a significant improvement in infraorbital hyperpigmentation at day 60 (P = 0.16). The picosecond 755 nm alexandrite laser significantly improved infraorbital hyperpigmentation by day 42, with improvement maintained through day 132 (P = 0.07 and 0.00001, respectively). Adverse events were mild and temporary., Conclusion: A single treatment with the fractionated picosecond 1,064/532 nm lasers did not produce a significant improvement in infraorbital hyperpigmentation. A series of three treatments with the fractionated picosecond 755 nm laser resulted in significant improvement in hyperpigmentation. Lasers Surg. Med. 50:45-50, 2018. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: There is conflicting evidence regarding the oncological impact of anastomotic leak following colorectal cancer surgery. This study aims to test the hypothesis that anastomotic leak is independently associated with local recurrence and overall and cancer-specific survival., Methods: Analysis of prospectively collected data from multiple centres in Victoria between 1988 and 2015 including all patients who underwent colon or rectal resection for cancer with anastomosis was presented. Overall and cancer-specific survival rates and rates of local recurrence were compared using Cox regression analysis., Results: A total of 4892 patients were included, of which 2856 had completed 5-year follow-up. The overall anastomotic leak rate was 4.0%. Cox regression analysis accounting for differences in age, sex, body mass index, American Society of Anesthesiologists score and tumour stage demonstrated that anastomotic leak was associated with significantly worse 5-year overall survival (χ 2 = 6.459, P = 0.011) for colon cancer, but only if early deaths were included. There was no difference in 5-year colon cancer-specific survival (χ 2 = 0.582, P = 0.446) or local recurrence (χ 2 = 0.735, P = 0.391). For rectal cancer, there was no difference in 5-year overall survival (χ 2 = 0.266, P = 0.606), cancer-specific survival (χ 2 = 0.008, P = 0.928) or local recurrence (χ 2 = 2.192, P = 0.139)., Conclusion: Anastomotic leak may reduce 5-year overall survival in colon cancer patients but does not appear to influence the 5-year overall survival in rectal cancer patients. There was no effect on local recurrence or cancer-specific survival., (© 2016 Royal Australasian College of Surgeons.)

Background: Both subsurface monopolar radiofrequency (SMRF) and microfocused ultrasound with visualization (MFU-V) have demonstrated the ability to lift and tighten the neck. No head-to-head comparison study exists of these 2 technologies., Objective: To compare the efficacy and safety of SMRF and MFU-V for the lifting and tightening of neck., Materials and Methods: Twenty subjects aged from 18 to 65 with moderate neck skin laxity were randomized to receive either one treatment of SMRF or MFU-V., Results: At Days 0, 30, 90, and 180, the mean (SD) investigator-assessed Neck Laxity Grade was 2.7 (0.67), 2.1 (1.1), 1.6 (1.2), and 0.86 (0.7), respectively, for patients treated with SMRF, and 2.8 (0.63), 2.4 (1.07), 1.5 (0.53), and 1.4 (0.7), respectively, for those treated with MFU-V. Both SMRF and MFU-V led to a significant decrease in the mean investigator-assessed Neck Laxity Grade by Day 90 and persistent to Day 180. Subject assessment of firmness, texture, and laxity also significantly improved by Day 90 and persistent to Day 180. Adverse events were mild and transient., Conclusion: There were no were statistically significant differences between SMRF and MFU-V in investigator-assessed and patient-assessed measures of neck laxity, patient satisfaction, and adverse events. Microfocused ultrasound with visualization was associated with more procedural pain.

Purpose: Though hydroquinone (HQ) remains the gold standard for treatment of hyperpigmentation, concerns about its safety have prompted the development of HQ-free topical skin lightening systems., Objective: To compare the efficacy and tolerability of a new HQ-free system and a popular HQ-based system for the improvement of facial hyperpigmentation and photoaging in darker skin types., Methods: This investigator-blinded trial randomized 30 subjects of Fitzpatrick skin types III to VI with moderate to severe hyperpigmentation to a new 7-product HQ-free system or a 7-product HQ-based system for 12 weeks. At 4, 8, and 12 week follow-up visits, a blinded investigator assessed efficacy and tolerability using standardized scales. Subjects also performed a self-assessment at each visit., Summary: Both the HQ-free and HQ-based systems produced significant improvements in Overall Hyperpigmentation that were sustained through week 12 (P=0.008, 0.0003). The HQ-based system demonstrated better improvement in overall hyperpigmentation at weeks 4, 8, 12 (P=0.01, 0.001, 0.003, respectively). Mottled Pigmentation Area Severity Index (MoPASI) scores improved with both systems (P=0.02, 0.01), with no statistically significant differences between the two treatment groups. Subject-rated hyperpigmentation was not different between groups. Subjects reported significantly more discomfort with the HQ-free system at week 8 (P=0.02); otherwise, measures of irritation were the same between groups. All irritation was described as mild to moderate. At week 12, 100% of subjects in the HQ-free group and 92.3% of subjects in the HQ-based group were satisfied with their outcome., Conclusion: Both a new HQ-free skincare system and a widely-available HQ-based system improved hyperpigmentation in Fitzpatrick skin types III to VI. Though the HQ-based system produced greater improvement in hyperpigmentation when compared to the HQ-free system, there was no difference in MoPASI scores between the treatment groups. Subjects were satisfied with both treatments and reported only mild to moderate irritation using either system.

J Drugs Dermatol. 2017;16(11):1127-1132.

Background and Objective: Following photodynamic therapy with 5-aminolevulinic acid (ALA-PDT), patients experience inflammation that may be partially attributable to H1 histamine receptor activation. The objective of this study was to evaluate the impact of antihistamines upon adverse effects following ALA-PDT., Study Design/materials and Methods: This was a randomized, placebo-controlled clinical trial conducted at a single study site. Twenty subjects with facial actinic keratoses were randomized to ALA-PDT plus cetirizine 10 mg (n = 10) versus placebo daily (n = 10) from 3 days pre-treatment to 3 days post-treatment for a total of 7 days. Signs of inflammation including erythema, edema, crusting, exudation, vesiculation, and erosion were evaluated on post-treatment days 1, 2, 3, 7, 30, 90, and 180. Actinic keratosis counts, investigator-rated Global Assessment Improvement Score (GAIS), healing, tolerability, and subject satisfaction were also assessed., Results: Erythema, edema, crusting, exudation, vesiculation, and erosion were not different between treatment groups. Actinic keratoses were significantly reduced by day 30 in both the antihistamine and placebo groups (P = 0.01 and 0.0009, respectively), with results sustained to day 60 in the antihistamine group and day 180 for the placebo group. However, counts were not different between groups at any time point. Investigator-rated GAIS, subject satisfaction, healing, and tolerability were similar between treatment groups., Conclusion: This study suggests that while H1 antihistamines do not impair the efficacy of ALA-PDT, they also do not relieve post-treatment inflammation and discomfort. Lasers Surg. Med. 49:738-742, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Benthic marine suspension feeders provide an important link between benthic and pelagic ecosystems. The strength of this link is determined by suspension-feeding rates. Many studies have measured suspension-feeding rates using indirect clearance-rate methods, which are based on the depletion of suspended particles. Direct methods that measure the flow of water itself are less common, but they can be more broadly applied because, unlike indirect methods, direct methods are not affected by properties of the cleared particles. We present pumping rates for three species of suspension feeders, the clams Mya arenaria and Mercenaria mercenaria and the tunicate Ciona intestinalis , measured using a direct method based on particle image velocimetry (PIV). Past uses of PIV in suspension-feeding studies have been limited by strong laser reflections that interfere with velocity measurements proximate to the siphon. We used a new approach based on fitting PIV-based velocity profile measurements to theoretical profiles from computational fluid dynamic (CFD) models, which allowed us to calculate inhalant siphon Reynolds numbers ( Re ). We used these inhalant Re and measurements of siphon diameters to calculate exhalant Re , pumping rates, and mean inlet and outlet velocities. For the three species studied, inhalant Re ranged from 8 to 520, and exhalant Re ranged from 15 to 1073. Volumetric pumping rates ranged from 1.7 to 7.4 l h -1 for M . arenaria , 0.3 to 3.6 l h -1 for M . m ercenaria and 0.07 to 0.97 l h -1 for C . intestinalis We also used CFD models based on measured pumping rates to calculate capture regions, which reveal the spatial extent of pumped water. Combining PIV data with CFD models may be a valuable approach for future suspension-feeding studies., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Purpose: Mutation of BRAF at the valine 600 residue occurs in approximately 10% of colorectal cancers, a group with particularly poor prognosis. The response of BRAF mutant colorectal cancer to recent targeted strategies such as anti-BRAF or combinations with MEK and EGFR inhibitors remains limited and highly heterogeneous within BRAF V600E cohorts. There is clearly an unmet need in understanding the biology of BRAF V600E colorectal cancers and potential subgroups within this population., Experimental Design: In the biggest yet reported cohort of 218 BRAF V600E with gene expression data, we performed unsupervised clustering using non-negative matrix factorization to identify gene expression-based subgroups and characterized pathway activation., Results: We found strong support for a split into two distinct groups, called BM1 and BM2. These subtypes are independent of MSI status, PI3K mutation, gender, and sidedness. Pathway analyses revealed that BM1 is characterized by KRAS/AKT pathway activation, mTOR/4EBP deregulation, and EMT whereas BM2 displays important deregulation of the cell cycle. Proteomics data validated these observations as BM1 is characterized by high phosphorylation levels of AKT and 4EBP1, and BM2 patients display high CDK1 and low cyclin D1 levels. We provide a global assessment of gene expression motifs that differentiate BRAF V600E subtypes from other colorectal cancers., Conclusions: We suggest that BRAF mutant patients should not be considered as having a unique biology and provide an in depth characterization of heterogeneous motifs that may be exploited for drug targeting. Clin Cancer Res; 23(1); 104-15. ©2016 AACR., (©2016 American Association for Cancer Research.)

Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL). Age-adjusted RTL was analyzed against germline variants in telomere biology genes, chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), TP53, KRAS, BRAF mutations and clinical outcomes. In 509 adenoma or CRC patients, nRTL decreased with advancing age. Female gender, proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL. Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases. Age-adjusted nRTL and cRTL were independently associated with tumor stage, decreasing from adenoma to stage III and leveling out or increasing from stage III to IV, respectively. Cancer MSI, CIMP, TP53, KRAS and BRAF status were not related to nRTL or cRTL. Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs, while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks. Age-adjusted nRTL, cRTL or cRTL:nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC. Taken together, our data show that both normal mucosa and tumor RTL are independently associated with CRC progression, and highlight divergent associations of CRC telomere length with tumor CIN profiles., Competing Interests: No conflicts of interest to disclose.

Purpose: Resource limitations are a concern in most modern public hospital systems. The aim of this study is to prospectively quantify the total caseload of a tertiary colorectal surgery unit to identify areas of redundancy., Methods: Data was collected prospectively at all points of clinical care (outpatient clinic, inpatient referrals, operating theatre and endoscopy) between March 2014 and March 2015 using specifically designed templates. The final data was analysed using descriptive statistics., Results: During the study period, 4012 patient episodes were recorded: 2871 in outpatient clinic, 186 as emergency patient referrals, 541 at colonoscopy and 414 at surgery. The largest component of the caseload was made up primarily of colonoscopy results follow-up, protocol review for previous cancer or polyps and post-operative review. Sixty-eight percent of these episodes did not result in any active intervention such as further tests or surgery. Most new outpatient referrals were undifferentiated, with the most common indications being minor rectal bleeding, non-specific gastrointestinal symptoms, and minor non-bleeding anorectal problems. Of the new referrals, 56 % were booked for a colonoscopy, and only 13.3 % were booked directly for elective surgery., Conclusion: A large component of the caseload of a tertiary colorectal surgery unit is made up of post-colonoscopy, post-operative, and surveillance protocol follow-up, with a significant proportion of patients not requiring any active intervention. The majority of new referrals are undifferentiated and result in a low rate of direct booking for operative intervention. Rationalisation of this resource using evidence-based methods could reduce redundancy, workload, and cost.