Excess Dietary Sugar Alters Colonocyte Metabolism and Impairs the Proliferative Response to Damage.

BACKGROUND & AIMS: The colonic epithelium requires continuous renewal by crypt resident intestinal stem cells (ISCs) and transit-amplifying (TA) cells to maintain barrier integrity, especially after inflammatory damage. The diet of high-income countries contains increasing amounts of sugar, such as sucrose. ISCs and TA cells are sensitive to dietary metabolites, but whether excess sugar affects their function directly is unknown. METHODS: Here, we used a combination of 3-dimensional colonoids and a mouse model of colon damage/repair (dextran sodium sulfate colitis) to show the direct effect of sugar on the transcriptional, metabolic, and regenerative functions of crypt ISCs and TA cells. RESULTS: We show that high-sugar conditions directly limit murine and human colonoid development, which is associated with a reduction in the expression of proliferative genes, adenosine triphosphate levels, and the accumulation of pyruvate. Treatment of colonoids with dichloroacetate, which forces pyruvate into the tricarboxylic acid cycle, restored their growth. In concert, dextran sodium sulfate treatment of mice fed a high-sugar diet led to massive irreparable damage that was independent of the colonic microbiota and its metabolites. Analyses on crypt cells from high-sucrose-fed mice showed a reduction in the expression of ISC genes, impeded proliferative potential, and increased glycolytic potential without a commensurate increase in aerobic respiration. CONCLUSIONS: Taken together, our results indicate that short-term, excess dietary sucrose can directly modulate intestinal crypt cell metabolism and inhibit ISC/TA cell regenerative proliferation. This knowledge may inform diets that better support the treatment of acute intestinal injury.

Key measurement concepts and appropriate clinical outcome assessments in pediatric achondroplasia clinical trials.

BACKGROUND: This study aimed to identify fit-for-purpose clinical outcome assessments (COAs) to evaluate physical function, as well as social and emotional well-being in clinical trials enrolling a pediatric population with achondroplasia. Qualitative interviews lasting up to 90 min were conducted in the US with children/adolescents with achondroplasia and/or their caregivers. Interviews utilized concept elicitation methodology to explore experiences and priorities for treatment outcomes. Cognitive debriefing methodology explored relevance and understanding of selected COAs. RESULTS: Interviews (N = 36) were conducted with caregivers of children age 0-2 years (n = 8) and 3-7 years (n = 7) and child/caregiver dyads with children age 8-11 years (n = 15) and 12-17 years (n = 6). Children/caregivers identified pain, short stature, impacts on physical functioning, and impacts on well-being (e.g. negative attention/comments) as key bothersome aspects of achondroplasia. Caregivers considered an increase in height (n = 9/14, 64%) and an improvement in limb proportion (n = 11/14, 71%) as successful treatment outcomes. The Childhood Health Assessment Questionnaire (CHAQ) and Quality of Life in Short Stature Youth (QoLISSY-Brief) were cognitively debriefed. CHAQ items evaluating activities, reaching, and hygiene were most relevant. QoLISSY-Brief items evaluating reaching, height bother, being treated differently, and height preventing doing things others could were most relevant. The CHAQ and QoLISSY-Brief instructions, item wording, response scales/options and recall period were well understood by caregivers and adolescents age 12-17. Some children aged 8-11 had difficulty reading, understanding, or required caregiver input. Feedback informed minor amendments to the CHAQ and the addition of a 7-day recall period to the QoLISSY-Brief. These amendments were subsequently reviewed and confirmed in N = 12 interviews with caregivers of children age 0-11 (n = 9) and adolescents age 12-17 (n = 3). CONCLUSIONS: Achondroplasia impacts physical functioning and emotional/social well-being. An increase in height and improvement in limb proportion are considered to be important treatment outcomes, but children/adolescents and their caregivers expect that a successful treatment should also improve important functional outcomes such as reach. The CHAQ (adapted for achondroplasia) and QoLISSY-Brief are relevant and appropriate measures of physical function and emotional/social well-being for pediatric achondroplasia trials; patient-report is recommended for age 12-17 years and caregiver-report is recommended for age 0-11 years.

Cost and clinical benefit of imaging surveillance after treatment for breast implant-associated anaplastic large cell lymphoma (BIA-ALCL).

Recent UK guidelines recommend that surveillance imaging should not be offered to patients who have undergone treatment for breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) unless clinically indicated. The aim of this study was to explore the evolving practice at a tertiary referral unit and quantify the direct economic costs (DEC) associated with post-treatment BIA-ALCL routine radiological surveillance prior to adoption of the guidelines. Eleven patients were treated for BIA-ALCL between 2015 and 2020. At a median follow-up of 38 months (IQR 12-47) there were no local or distant relapses. Two patients did not have any radiological surveillance and 1 had follow-up elsewhere. The remaining 8 patients had a combination of positron emission tomography/computed tomography (PET/CT) (n = 10), CT (n = 2), breast ultrasound (n = 6), mammogram (n = 4) and breast magnetic resonance imaging (MRI) (n = 1) as routine imaging follow-up not guided by clinical concerns. Total cost of imaging was £10,396 (€12,257) with a median cost of £1953 (€2304) per patient [IQR £526-2029 (€621-2394)]. This cost could have been saved based on current guidelines recommending no routine surveillance for asymptomatic patients.

Capturing Gas Fluxes on Your Phone: An iOS- and Android-based Data-Logging Setup for EGM-4 Environmental Gas Monitoring Systems.

Mobile devices have become increasingly important for field monitoring to improve data capture efficiency, increase storage capacity, and replace heavy equipment. We introduce a quick and straightforward protocol to capture greenhouse gas (GHG) emission rates on mobile devices. We developed our setup on the widely used infrared gas analyzer (IRGA) EGM-4 by PP Systems. This IRGA has a limited internal storage capacity and requires an external device such as a laptop to conduct even modest field sampling. Furthermore, when raw data storage is required, carbon dioxide concentration resolution is reduced by the internal EGM-4 software settings, making the equipment less suitable for high-frequency measurements. Our protocol lets the user bring either an iOS or Android mobile device in to the field to connect to the EGM-4's data stream. For both platforms, a mobile console application was used to read, log, and share flux data. The raw data can be processed in either Python, R, or Matlab using the provided scripts that give the user flexibility to amend further postprocessing steps to obtain GHG fluxes. We demonstrate the flexible applicability of mobile devices for field recording and show that a cost-effective solution can enhance the operational life of superseded field equipment while also increasing the quality of the captured data.

The Use of Hydrodissection in Nipple- and Skin-sparing Mastectomy: A Retrospective Cohort Study.

Hydrodissection (HD) is a method to create a subcutaneous and prepectoral plane during mastectomy using a mixture of crystalloid solution with local anesthetic and epinephrine. The aim of this study was to evaluate postoperative complications and surgical outcomes of this technique compared with standard mastectomy. METHODS: This is a retrospective cohort study of patients who underwent bilateral risk-reducing, nipple-sparing mastectomy and immediate implant-based reconstruction through an inframammary crease incision either with standard electrocautery (control group) or HD (HD group) between January 2013 and January 2017. Patient demographics, procedural details, surgical outcomes, and complications were compared using nonparametric statistical tests and logistic regression analysis. RESULTS: Forty-one patients (82 nipple-sparing mastectomies) were analyzed (23 patients in the HD group and 18 in the control group). Patients' demographics were similar for both groups. Surgical time was shorter with HD compared with standard mastectomy (median 168 versus 207.5 minutes, P = 0.016) with shorter median hospital stay (2 versus 2.5 days, P = 0.033). Complication rates were similar in both groups, and fewer patients in the HD group required Coleman fat transfer to improve cosmesis (12 versus 3, P = 0.003). CONCLUSIONS: HD mastectomy is a safe alternative to standard technique in selected patients. Further surgical research to explore the role of HD in a wider clinical setting is warranted.

Introducing robotic radical hysterectomy for stage 1bi cervical cancer-A prospective evaluation of clinical and economic outcomes in a single UK institution.

BACKGROUND: We have assessed the impact of introducing robotics for a stage 1b cervical cancer service on laparotomy rates, complications, and costs. METHODS: Data were collected prospectively from 90 consecutive patients who had a radical hysterectomy between 1 April 2010 and 31 December 2017. RESULTS: There were 37 women before the first robotic procedure and 53 after. The laparotomy rate reduced from 75% (9/12) in 2010 to 0% (0/18) in 2017. The length of stay reduced from 6 days (range 3-39) to 3 days (range 1-15) (P < 0.0001). The complication rate before robotics was 68% (25/37) compared with 45% (24/53) afterwards (P = 0.0493). The blood transfusion rate reduced from 43% (16/37) to 11% (6/53) (P = 0.0007). There were no differences between the total costs before and after the introduction of robotics or between each route. CONCLUSIONS: In this series, introducing robotics for cervical carcinoma reduced hospital stay and complications. No cost differences were demonstrated.

The Memokath-051 Stent for the Treatment of Ureteric Obstruction: A NICE Medical Technology Guidance.

Memokath-051 is a thermo-expandable, nickel-titanium alloy spiral stent used to treat ureteric obstruction resulting from malignant or benign strictures. The National Institute for Health and Care Excellence (NICE) selected Memokath-051 for evaluation. The company, PNN Medical, claimed Memokath-051 has clinical superiority and cost savings compared with double-J stents. It identified five studies reporting clinical evidence on Memokath-051 and constructed a de novo cost model comparing Memokath-051 to double-J stents. Results indicated that Memokath-051 generated cost savings of £4156 per patient over 2.5 years. The External Assessment Centre (EAC) critiqued the company's submission and completed substantial additional work. Sixteen studies were identified assessing Memokath-051 and all listed comparators in the scope (double-J stents, reconstructive surgery and metallic and alloy stents) except nephrostomy. Similar success rates were reported for Memokath-051 compared with double-J and Resonance stents and worse outcomes compared with other options with evidence available. The EAC updated the company's cost model structure and modified several inputs. The EAC's model estimated that Memokath-051 generated savings of at least £1619 per patient over 5 years compared with double-J stents, was cost neutral compared with other metallic stents and was cost saving compared with surgery up to month 55. Overall, Memokath-051 is likely to be cost saving in patients not indicated for reconstructive surgery and those expected to require a ureteral stent for at least 30 months. The Medical Technologies Advisory Committee (MTAC) reviewed the evidence and supported the case for adoption, issuing partially supportive recommendations published after public consultation as Medical Technologies Guidance 35.

Evaluation of prognostic models developed using standardised image features from different PET automated segmentation methods.

BACKGROUND: Prognosis in oesophageal cancer (OC) is poor. The 5-year overall survival (OS) rate is approximately 15%. Personalised medicine is hoped to increase the 5- and 10-year OS rates. Quantitative analysis of PET is gaining substantial interest in prognostic research but requires the accurate definition of the metabolic tumour volume. This study compares prognostic models developed in the same patient cohort using individual PET segmentation algorithms and assesses the impact on patient risk stratification. Consecutive patients (n = 427) with biopsy-proven OC were included in final analysis. All patients were staged with PET/CT between September 2010 and July 2016. Nine automatic PET segmentation methods were studied. All tumour contours were subjectively analysed for accuracy, and segmentation methods with < 90% accuracy were excluded. Standardised image features were calculated, and a series of prognostic models were developed using identical clinical data. The proportion of patients changing risk classification group were calculated. RESULTS: Out of nine PET segmentation methods studied, clustering means (KM2), general clustering means (GCM3), adaptive thresholding (AT) and watershed thresholding (WT) methods were included for analysis. Known clinical prognostic factors (age, treatment and staging) were significant in all of the developed prognostic models. AT and KM2 segmentation methods developed identical prognostic models. Patient risk stratification was dependent on the segmentation method used to develop the prognostic model with up to 73 patients (17.1%) changing risk stratification group. CONCLUSION: Prognostic models incorporating quantitative image features are dependent on the method used to delineate the primary tumour. This has a subsequent effect on risk stratification, with patients changing groups depending on the image segmentation method used.

The effect of obesity on clinical and economic outcomes in robotic endometrial cancer surgery.

The aim of this study was to compare the financial and clinical outcomes in robotic-assisted laparoscopic surgery for primary endometrial cancer between obese and nonobese women. The hospital finance department assessed the total admission costs for robotic surgery for endometrial cancer in 54 women. This included a subanalysis for costs over nine areas (ward and clinics, drugs and pharmacy, medical staff, theaters, blood products, imaging, pathology, rehabilitation therapy, and high dependency costs). Furthermore, a prospective collection of morbidity and surgical outcome data was performed. The study group included 21 nonobese and 33 obese women (body mass index >30). Obese women were more likely to stay for more than one night in hospital (20/33 [60.6%] compared to 4/21 [19.0%], P=0.032) and to have high dependency care (25/33 [75.8%] compared to 10/21 [47.6%], P=0.032). Theater time was on average 35 min longer (95% confidence interval [CI] 5-65 min, P=0.0252). Both the groups were comparable for comorbidities except for the presence of diabetes being present in the obese group (13/33 [39.4%] compared to 0/21 [0.0%], P=0.007). There were six Clavien-Dindo grade II complications in the obese group and two in the nonobese group. The average overall costs were £1,852 greater (95% CI £431-£3,277, P=0.012) in the obese group. Diabetes and hypertension were associated with increased costs, but obesity was the only independent variable. In conclusion, greater resource should be allocated to obese women undergoing primary surgery for endometrial cancer.

Introducing robotic surgery into an endometrial cancer service--a prospective evaluation of clinical and economic outcomes in a UK institution.

BACKGROUND: We have assessed how the introduction of robotics in a publicly funded endometrial cancer service affects clinical and economic outcomes. METHODS: The study included 196 women. Costs were divided into those for wards, high dependency, staffing, theatres, pharmacy, blood products, imaging, pathology and rehabilitation. Capital depreciation was included. RESULTS: Prior to the introduction of robotics, 78/130 (60.0%) cases were performed open, compared to 17/66 (25.8%) afterwards (p < 0.0001). The median operative time increased 37 min (95% CI 17-55 min; p = 0.0002); the median blood loss was 55 ml lower (95% CI 0-150 ml; p = 0.0181); the stay was 2 days shorter (95% CI 1-3; p < 0.0001). Complications reduced from 64/130 (49.2%) to 19/66 (28.8%) (p = 0.0045). Costs reduced from £11 476 to £10 274 (p = 0.0065). Conversions for 'straight stick' surgery were 18.2% (14/77) compared to 0.0% (0/24) for robotics (p = 0.0164). CONCLUSIONS: Introducing robotics resulted in fewer laparotomies, shorter stays, fewer complications and lower costs.

ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma.

Proinflammatory cytokines are frequently observed in the tumor microenvironment, and chronic inflammation is involved in cancer initiation and progression. We show that cytokine signaling through the receptor subunit GP130-IL6ST and the kinase JAK1 generates actomyosin contractility through Rho-kinase dependent signaling. This pathway generates contractile force in stromal fibroblasts to remodel the extracellular matrix to create tracks for collective migration of squamous carcinoma cells and provides the high levels of actomyosin contractility required for migration of individual melanoma cells in the rounded, "amoeboid" mode. Thus, cytokine signaling can generate actomyosin contractility in both stroma and tumor cells. Strikingly, actomyosin contractility itself positively modulates activity of the transcription factor STAT3 downstream of JAK1, demonstrating positive feedback within the signaling network.

Regulation of cell signalling by uPAR.

Urokinase-type plasminogen activator receptor (uPAR) expression is elevated during inflammation and tissue remodelling and in many human cancers, in which it frequently indicates poor prognosis. uPAR regulates proteolysis by binding the extracellular protease urokinase-type plasminogen activator (uPA; also known as urokinase) and also activates many intracellular signalling pathways. Coordination of extracellular matrix (ECM) proteolysis and cell signalling by uPAR underlies its important function in cell migration, proliferation and survival and makes it an attractive therapeutic target in cancer and inflammatory diseases. uPAR lacks transmembrane and intracellular domains and so requires transmembrane co-receptors for signalling. Integrins are essential uPAR signalling co-receptors and a second uPAR ligand, the ECM protein vitronectin, is also crucial for this process.

Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation.

The mechanisms involved in resistance to estrogen deprivation are of major importance for optimal patient therapy and the development of new drugs. Long term culture of MCF-7 cells in estrogen (E2)-depleted medium (long term estrogen deprivation; LTED) results in hypersensitivity to E2 coinciding with elevated levels of estrogen receptor (ER) alpha phosphorylated on Ser118 and MAPK, together with several of its downstream targets associated previously with ERalpha phosphorylation. Our data suggest elevated MAPK activity results from enhanced ERBB2 expression in the LTED cells versus the wild-type (wt), and treatment with the tyrosine kinase inhibitor ZD1839 revealed increased sensitivity in both transcription and proliferation assays. Similarly the MEK inhibitor U0126 decreased transcription and proliferation in the LTED cells and reduced their sensitivity to the proliferative effects of E2, while having no effect on the wt. However, the complete suppression of MAPK activity in the LTED cells did not inhibit ERalpha Ser118 phosphorylation suggesting that ER activity remained ligand-dependant. The LTED cells also expressed elevated levels of insulin-like growth factor-1R, and inhibition of phosphatidylinositol 3-kinase activity with LY294002 reduced basal ERalpha transactivation by 70% in the LTED cells compared with the wt. However, LY294002 had no effect on ERalpha Ser118 phosphorylation. These data suggest that although elevated levels of MAPK occur during LTED and influence the phenotype, this is unlikely to be the sole pathway operating to achieve adaptation.