Comparison of Stereotactic Body Radiotherapy Delivery Techniques for Early-Stage Lung Cancer Using Lung Toxicity Modeling

Purpose: Lung toxicity is a primary side effect in stereotactic radiotherapy (SBRT) for early-stage non-small cell lung cancer (NSCLC). We aimed to use a set of radiobiological models to evaluate and compare modern IMRT delivery techniques with three-dimensional conformal techniques for SBRT treatment of NSCLC in terms of lung toxicity, and aimed to compare the results from different radiobiologcal models. Methods: Ten early-stage NSCLC patients treated with SBRT were retrospectively selected. Five treatment plans were generated to deliver 50 Gy in five fractions to the planning target volume for each case: a helical tomotherapy (HT) plan, two three-dimensional cofnromal radiotherapy (3D-CRT) plans using 6-MV and 10-MV photon beams respectively, and two volumetric modulated arc therapy (VMAT) plans using one and two arc fields respectively. The lung RDV was calculated with three parallel functional sub-unit (FSU) models and two normal tissue complication probability (NTCP) models. Results: Both the HT and VMAT plans showed significantly higher contralateral mean lung dose and lower ipsilateral mean lung dose compared to the 3D-CRT plans. There was no statistically significant difference in terms of lung toxicities between the IMRT and 3D-CRT techniques using either the FSU models or the NTCP models. Based on both the FSU and the NTCP models, there was strong correlation between lung toxicity and the mean lung dose in SBRT treatment plans. Conclusions: Based on both the NTCP and parallel FSU models, both IMRT and traditional 3D-CRT delivery techniques could achieve comparable lung sparing inn SBRT treatment of early-stage lung cancer. However, the validity of the radiobiological model results should be checked by clinical data.

Organ and function preservation in gastrointestinal cancer: Current and future perspectives on endoscopic ablation

The escalating prevalence of gastrointestinal cancers underscores the urgency for transformative approaches.Current treatment costs amount to billions of dollars annually,combined with the risks and comorbidities associated with invasive surgery.This highlights the importance of less invasive alternatives with organ preservation being a central aspect of the treatment paradigm.The current standard of care typically involves neoadjuvant systemic therapy followed by surgical resection.There is a growing interest in organ preservation approaches by way of minimizing extensive surgical resections.Endoscopic ablation has proven to be useful in precursor lesions,as well as in palliative cases of unrese-ctable disease.More recently,there has been an increase in reports on the utility of adjunct endoscopic ablative techniques for downstaging disease as well as contributing to non-surgical complete clinical response.This expansive field within endoscopic oncology holds great potential for advancing patient care.By addressing challenges,fostering collaboration,and embracing technological advancements,the gastrointestinal cancer treatment paradigm can shift towards a more sustainable and patient-centric future emphasizing organ and function preservation.This editorial examines the evolving landscape of endoscopic ablation strategies,emphasizing their potential to improve patient outcomes.We briefly review current applications of endoscopic ablation in the esophagus,stomach,duodenum,pancreas,bile ducts,and colon.

Efficacy of adjuvant XELOX and FOLFOX6 chemotherapy after D2 dissection for gastric cancer

AIM: To compare the efficacy of capecitabine and oxaliplatin (XELOX) with 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX6) in gastric cancer patients after D2 dissection. METHODS: Between May 2004 and June 2010, patients in our gastric cancer database who underwent D2 dissection for gastric cancer at the First Affiliated Hospital of Sun Yat-Sen University were retrospectively analyzed. A total of 896 patients were enrolled into this study according to the established inclusion and exclusion criteria. Of these patients, 214 received the XELOX regimen, 48 received FOLFOX6 therapy and 634 patients underwent surgery only without chemotherapy. Overall survival was compared among the three groups using Cox regression and propensity score matchedpair analyses. RESULTS: Patients in the XELOX and FOLFOX6 groups were younger at the time of treatment (median age 55.2 years; 51.2 years vs 58.9 years), had more undifferentiated tumors (70.1%; 70.8% vs 61.4%), and more lymph node metastases (80.8%; 83.3% vs 57.7%), respectively. Overall 5-year survival was 57.3% in the XELOX group which was higher than that (47.5%) in the surgery only group (P = 0.062) and that (34.5%) in the FOLFOX6 group (P = 0.022). Multivariate analysis showed that XELOX therapy was an independent prognostic factor (hazard ratio = 0.564, P < 0.001). After propensity score adjustment, XELOX significantly increased overall 5-year survival compared to surgery only (58.2% vs 44.2%, P = 0.025) but not compared to FOLFOX6 therapy (48.5% vs 42.7%, P = 0.685). The incidence of grade 3/4 adverse reactions was similar between the XELOX and FOLFOX6 groups, and more patients suffered from hand-foot syndrome in the XELOX group (P = 0.018). CONCLUSION: Adjuvant XELOX therapy is associated with better survival in patients after D2 dissection, but does not result in a greater survival benefit compared with FOLFOX6 therapy.

Role of minimally invasive surgery for rectal cancer

Rectal cancer is one of the most common malignancies worldwide.Surgical resection for rectal cancer usually requires a proctectomy with respective lymphadenectomy(total mesorectal excision).This has traditionally been performed transabdominally through an open incision.Over the last thirty years,minimally invasive surgery platforms have rapidly evolved with the goal to accomplish the same quality rectal resection through a less invasive approach.There are currently three resective modalities that complement the traditional open operation:(1)Laparoscopic surgery;(2)Robotic surgery;and(3)Transanal total mesorectal excision.In addition,there are several platforms to carry out transluminal local excisions(without lymphadenectomy).Evidence on the various modalities is of mixed to moderate quality.It is unreasonable to expect a randomized comparison of all options in a single trial.This review aims at reviewing in detail the various techniques in regard to intra-/perioperative benchmarks,recovery and complications,oncological and functional outcomes.

Over-expression of fibroblast growth factor receptor 3 in human hepatocellular carcinoma

AIM: To describe the significant over-expression of fibroblast growth factor receptor 3 (FGFR3), which is a signal transduction and cell proliferation related gene in hepatocellular carcinoma (HCC).METHODS: Following DNA microarray, Northern blot and quantitative real-time PCR were employed to confirm FGFR3 expression difference in HCC tissues and surrounding non-neoplastic liver tissue. FGFR3 expression levels were further determined by immunohistochemical study in 43 cases of HCC.RESULTS: Northern blot results showed the significant over-expression of FGFR3 in HCC tissues, which was consistent with that from DNA microarray. Quantitative real-time PCR demonstrated that the mean ratio of FGFR3 mRNA to glyceraldehyde-3-phosphate dehydrogenase (GADPH) mRNA in HCC tissue was 0.250, whereas the ratio in non-neoplastic liver tissue was 0.014. Statistical analyses of 43 cases of HCC revealed that HCC scored higher than the matched non-neoplastic liver tissues.Examination of clinicopathological features revealed a strong correlation of over-expression of FGFR3 with poor tumor differentiation and high nuclear grade.CONCLUSION: Over-expression of FGFR3 may play an important role in liver carcinogenesis. FGFR3 may be an ideal candidate as a molecular marker in the diagnosis of HCC and a potential therapeutic target.

Impact of RAS and BRAF mutations on carcinoembryonic antigen production and pattern of colorectal metastases

AIM: To investigate the impact of RAS and BRAF mutations on the pattern of metastatic disease and carcinoembryonic antigen(CEA) production.METHODS: In this retrospective study, we investigated the impact of RAS and BRAF mutational status on pattern of metastatic disease and CEA production. Only patients presenting with a newly diagnosed metastatic colorectal cancer(CRC) were included. Patients' characteristics, primary tumor location, site of metastatic disease and CEA at presentation were compared between those with and without RAS and BRAF mutations.RESULTS: Among 174 patients, mutations in KRAS, NRAS and BRAF were detected in 47%, 3% and 6% respectively. RAS mutations(KRAS and NRAS) were more likely to be found in African American patients(87% vs 13%; P value = 0.0158). RAS mutations were associated with a higher likelihood of a normal CEA(< 5 ng/mL) at presentation. BRAF mutations were more likely to occur in females. We were not able to confirm any association between mutational status and site of metastatic disease at initial diagnosis.CONCLUSION: No association was found between RAS and BRAF mutations and sites of metastatic disease at the time of initial diagnosis in our cohort. Patients with RAS mutations were more likely to present with CEA levels < 5 ng/mL. These findings may have clinical implications on surveillance strategies for RAS mutant patients with earlier stages of CRC.

World Journal of GastroenterologyDevelopment and validation of a risk prediction score for the severity of acute hypertriglyceridemic pancreatitis in Chinese patients

BACKGROUND The frequency of acute hypertriglyceridemic pancreatitis(AHTGP) is increasing worldwide. AHTGP may be associated with a more severe clinical course and greater mortality than pancreatitis caused by other causes. Early identification of patients with severe inclination is essential for clinical decision-making and improving prognosis. Therefore, we first developed and validated a risk prediction score for the severity of AHTGP in Chinese patients.AIM To develop and validate a risk prediction score for the severity of AHTGP in Chinese patients.METHODS We performed a retrospective study including 243 patients with AHTGP. Patients were randomly divided into a development cohort(n = 170) and a validation cohort(n = 73). Least absolute shrinkage and selection operator and logistic regression were used to screen 42 potential predictive variables to construct a risk score for the severity of AHTGP. We evaluated the performance of the nomogram and compared it with existing scoring systems. Last, we used the best cutoff value(88.16) for severe acute pancreatitis(SAP) to determine the risk stratification classification.RESULTS Age, the reduction in apolipoprotein A1 and the presence of pleural effusion were independent risk factors for SAP and were used to construct the nomogram(risk prediction score referred to as AAP). The concordance index of the nomogram in the development and validation groups was 0.930 and 0.928, respectively. Calibration plots demonstrate excellent agreement between the predicted and actual probabilities in SAP patients. The area under the curve of the nomogram(0.929) was better than those of the Bedside Index of Severity in AP(BISAP), Ranson, Acute Physiology and Chronic Health Evaluation(APACHE II), modified computed tomography severity index(MCTSI), and early achievable severity index scores(0.852, 0.825, 0.807, 0.831 and 0.807, respectively). In comparison with these scores, the integrated discrimination improvement and decision curve analysis showed improved accuracy in predicting SAP and better net benefits for clinical decisions. Receiver operating characteristic curve analysis was used to determine risk stratification classification for AHTGP by dividing patients into high-risk and low-risk groups according to the best cutoff value(88.16). The high-risk group(> 88.16) was closely related to the appearance of local and systemic complications, Ranson score ≥ 3, BISAP score ≥ 3, MCTSI score ≥4, APACHE II score ≥ 8, C-reactive protein level ≥ 190, and length of hospital stay.CONCLUSION The nomogram could help identify AHTGP patients who are likely to develop SAP at an early stage, which is of great value in guiding clinical decisions.

Functional analysis of helicase and three tandem HRDC domains of RecQ in Deinococcus radiodurans

RecQ is a highly conserved helicase necessary for maintaining genome stability in all organisms. Genome comparison showed that a homologue of RecQ in Deinococcus radiodurans designated as DR1289 is a member of RecQ family with unusual domain arrangement: a helicase domain, an RecQ C-terminal domain, and surprisingly three HRDC domain repeats, whose func-tion, however, remains obscure currently. Using an insertion deletion, we discovered that the DRRecQ mutation causes an increase in gamma radiation, hydroxyurea and mitomycine C and UV sensitivity. Using the shuttle plasmid pRADK, we complemented various domains of the D. radiodurans RecQ (DRRecQ) to the mutant in vivo. Results suggested that both the helicase and helicase-and-RNase-D-C-terminal (HRDC) domains are essential for complementing several phenotypes. The complementation and biochemical function of DRRecQ variants with different domains truncated in vitro suggested that both the helicase and three HRDC domains are necessary for RecQ functions in D. radiodurans, while three HRDC domains have a synergistic effect on the whole function. Our finding leads to the hypothesis that the RecF recombination pathway is likely a primary path of double strand break repair in this well-known radioresistant organism.

Long-term survival of patients with stage Ⅱ and Ⅲgastric cancer who underwent gastrectomy with inadequate nodal assessment

BACKGROUND Gastric cancer is an aggressive disease with frequent lymph node(LN)involvement.The NCCN recommends a D2 lymphadenectomy and the harvesting of at least 16 LNs.This threshold has been the subject of great debate,not only for the extent of surgery but also for more appropriate staging.The reclassification of stage IIB through IIIC based on N3b nodal staging in the eighth edition of the American Joint Committee on Cancer(AJCC)staging system highlights the efforts to more accurately discriminate survival expectancy based on nodal number.Furthermore,studies have suggested that pathologic assessment of 30 or more LNs improve prognostic accuracy and is required for proper staging of gastriccancer.AIM To evaluate the long-term survival of advanced gastric cancer patients who deviated from expected survival curves because of inadequate nodal evaluation.METHODS Eligible patients were identified from the Surveillance,Epidemiology,and End Results database.Those with stage II-III gastric cancer were considered for inclusion.Three groups were compared based on the number of analyzed LNs.They were inadequate LN assessment(ILA,<16 LNs),adequate LN assessment(ALA,16-29 LNs),and optimal LN assessment(OLA,≥30 LNs).The main outcomes were overall survival(OS)and cancer-specific survival.Data were analyzed by the Kaplan-Meier product-limit method,log-rank test,hazard risk,and Cox proportional univariate and multivariate models.Propensity score matching(PSM)was used to compare the ALA and OLA groups.RESULTS The analysis included 11607 patients.Most had advanced T stages(T3=48%;T4=42%).The pathological AJCC stage distribution was IIA=22%,IIB=18%,IIIA=26%,IIIB=22%,and IIIC=12%.The overall sample divided by the study objective included ILA(50%),ALA(35%),and OLA(15%).Median OS was 24 mo for the ILA group,29 mo for the ALA group,and 34 mo for the OLA group(P<0.001).Univariate analysis showed that the ALA and OLA groups had better OS than the ILA group[ALA hazard ratio(HR)=0.84,95%confidence interval(CI):0.79-0.88,P<0.001 and OLA HR=0.73,95%CI:0.68-0.79,P<0.001].The OS outcome was confirmed by multivariate analysis(ALA HR=0.68,95%CI:0.64-0.71,P<0.001 and OLA:HR=0.48,95%CI:0.44-0.52,P<0.001).A 1:1 PSM analysis in 3428 patients found that the OLA group had better survival than the ALA group(OS:OLA median=34 mo vs ALA median=26 mo,P<0.001,which was confirmed by univariate analysis(HR=0.81,95%CI:0.75-0.89,P<0.001)and multivariate analysis:(HR=0.71,95%CI:0.65-0.78,P<0.001).CONCLUSION Proper nodal staging is a critical issue in gastric cancer.Assessment of an inadequate number of LNs places patients at high risk of adverse long-term survival outcomes.

Association of insulin resistance with serum ferritin and aminotransferases-iron hypothesis

AIM: To investigate the relationship of iron indices with diabetes mellitus(DM) in those without hemochromatosis.METHODS: This cross-sectional study examined data collected during the Third National Health and Nutrition Examination Survey(NHANES III). Only those who fasted properly and were not anemic with transferrin saturation < 45% were included(n = 6849). Insulin sensitivity and beta cell function were calculated from fasting glucose and insulin concentrations. Indices of iron metabolism were examined in the presence or absence of DM. We examined the relationship of insulin sensitivity and beta cell function with serum ferritin concentration. The influence of C-reactive protein and liver enzymes was also investigated.RESULTS: Serum ferritin concentration was significantly higher in diabetic subjects(P = 0.0001 to< 0.000001). The difference remained significant after adjustment for age, body mass index, alcohol consumption, and mineral/iron supplement(P = 0.03 to< 0.000001). In those who did not take insulin, serum ferritin concentration was negatively associated with insulin sensitivity(P = 0.05 to 0.00001), but not with beta cell function. The alanine aminotransferase was correlated with serum ferritin concentration(P = 0.02 to< 0.000001) but not with insulin sensitivity, suggesting the role of the liver in iron-associated insulin resistance.CONCLUSION: As most of diabetes is type 2 diabetes and insulin resistance is a cardinal feature of type 2diabetes, disordered iron metabolism could play a role in the pathogenesis of insulin resistance and type 2diabetes through its effect on liver function.

Role of hepatitis A virus in diabetes mellitus

BACKGROUND Although much information is available regarding hepatitis C virus infection and diabetes,less is known about the relationship between hepatitis A virus(HAV)infection and diabetes.AIM To examine the roles of HAV in diabetes risk.METHODS This cross-sectional study population included data from the National Health and Nutrition Examination Survey collected between 2005-2012.Adult subjects(≥20 years old)with available body mass index measurements,defined diabetes status,history of HAV vaccination,and HAV serology were included.HAV vaccination was based on self-reported history.Successful HAV immunization was defined as the presence of both vaccination and anti-HAV antibody.HAV infection was defined by the absence of vaccination but presence of anti-hepatitis A antibody.The odds ratio(OR)for diabetes with 95%confidence intervals(95%CI)was calculated for each HAV status and then adjusted for covariates.Sensitivity tests,based on different definitions of diabetes,were performed to verify the results.RESULTS Among 19942 subjects,4229 subjects(21.21%)received HAV vaccination and HAV antibody was present in 9224 subjects(46.25%).Although HAV infection was associated with an increased risk of diabetes(OR:1.13;95%CI:1.08-1.18),HAV vaccination was not associated with diabetes(OR:1.06;95%CI:0.95-1.18),and successful HAV immunization had no impact on the risk of diabetes(OR:1.11;95%CI:0.97-1.27).Thus,HAV infection was an unlikely cause of diabetes.Alternatively,in non-vaccinated subjects,diabetes increased the risk of HAV infection by 40%(OR:1.40,95%CI:1.27-1.54).CONCLUSION An association between HAV infection and diabetes is observed which is best explained by an increased risk of HAV infection in diabetic patients.Diabetic subjects are more susceptible to HAV.Thus,HAV vaccination is highly recommended in diabetic patients.

Conundrum of vitamin D on glucose and fuel homeostasis

As an endocrine hormone,vitamin D plays an important role in bone health and calcium homeostasis.Over the past two decades,the non-calcemic effects of vitamin D were extensively examined.Although the effect of vitamin D on beta cell function were known for some time,the effect of vitamin D on glucose and fuel homeostasis has attracted new interest among researchers.Yet,to date,studies remain inconclusive and controversial,in part,due to a lack of understanding of the threshold effects of vitamin D.In this review,a critical examination of interventional trials of vitamin D in prevention of diabetes is provided.Like use of vitamin D for bone loss,the benefits of vitamin D supplementation in diabetes prevention were observed in vitamin D-deficient subjects with serum 25-hydroxyvitamin D<50 nmol/L(20 ng/mL).The beneficial effect from vitamin D supplementation was not apparent in subjects with serum 25-hydroxyvitamin D>75 nmol/L(30 ng/mL).Furthermore,no benefit was noted in subjects that achieved serum 25-hydroxyvitamin D>100 nmol/L(40 ng/mL).Further studies are required to confirm these observations.

A computational model of the human glucose-insulin regulatory system

Objective：A computational model of insulin secretion and glucose metabolism for assisting the diagnosis of diabetes mellitus in clinical research is introduced.The proposed method for the estimation of parameters for a system of ordinary differential equations（ODEs）that represent the time course of plasma glucose and insulin concentrations during glucose tolerance test（GTT）in physiological studies is presented.The aim of this study was to explore how to interpret those laboratory glucose and insulin data as well as enhance the Ackerman mathematical model.Methods：Parameters estimation for a system of ODEs was performed by minimizing the sum of squared residuals（SSR）function,which quantifies the difference between theoretical model predictions and GTT＇s experimental observations.Our proposed perturbation search and multiple-shooting methods were applied during the estimating process.Results：Based on the Ackerman＇s published data,we estimated the key parameters by applying R-based iterative computer programs.As a result,the theoretically simulated curves perfectly matched the experimental data points.Our model showed that the estimated parameters,computed frequency and period values,were proven a good indicator of diabetes.Conclusion：The present paper introduces a computational algorithm to biomedical problems,particularly to endocrinology and metabolism fields,which involves two coupled differential equations with four parameters describing the glucose-insulin regulatory system that Ackerman proposed earlier.The enhanced approach may provide clinicians in endocrinology and metabolism field insight into the transition nature of human metabolic mechanism from normal to impaired glucose tolerance.

Comparison of open and closed hyperthermic intraperitoneal chemotherapy: Results from the United States hyperthermic intraperitoneal chemotherapy collaborative

BACKGROUND Cytoreductive surgery(CRS)with hyperthermic intraperitoneal chemotherapy(HIPEC)for peritoneal carcinomatosis can be performed in two ways:Open or closed abdominal technique.AIM To evaluate the impact of HIPEC method on post-operative and long-term survival outcomes.METHODS Patients undergoing CRS with HIPEC from 2000-2017 were identified in the United States HIPEC collaborative database.Post-operative,recurrence,and overall survival outcomes were compared between those who received open vs closed HIPEC.RESULTS Of the 1812 patients undergoing curative-intent CRS and HIPEC,372(21%)patients underwent open HIPEC and 1440(79%)underwent closed HIPEC.There was no difference in re-operation or severe complications between the two groups.Closed HIPEC had higher rates of 90-d readmission while open HIPEC had a higher rate of 90-d mortalities.On multi-variable analysis,closed HIPEC technique was not a significant predictor for overall survival(hazards ratio:0.75,95%confidence interval:0.51-1.10,P=0.14)or recurrence-free survival(hazards ratio:1.39,95%confidence interval:1.00-1.93,P=0.05)in the entire cohort.These findings remained consistent in the appendiceal and the colorectal subgroups.CONCLUSION In this multi-institutional analysis,the HIPEC method was not independently associated with relevant post-operative or long-term outcomes.HIPEC technique may be left to the discretion of the operating surgeon.

Accuracy of computed tomography in nodal staging of colon cancer patients

AIM: To predict node-positive disease in colon cancer using computed tomography(CT).METHODS: American Joint Committee on Cancer stage Ⅰ-Ⅲ colon cancer patients who underwent curavtiveintent colectomy between 2007-2010 were identified at a single comprehensive cancer center. All patients had preoperative CT scans with original radiology reports from referring institutions. CT images underwent blinded secondary review by a surgeon and a dedicated abdominal radiologist at our institution to identify pericolonic lymph nodes(LNs). Comparison of outside CT reports to our independent imaging review was performed in order to highlight differences in detection in actual clinical practice. CT reviews were compared with final pathology. Results of the outside radiologist review, secondary radiologist review, and surgeon review were compared with the final pathologic exam to determine sensitivity, specificity, positive and negative predictive values, false positive and negative rates, and accuracy of each review. Exclusion criteria included evidenceof metastatic disease on CT, rectal or appendiceal involvement, or absence of accompanying imaging from referring institutions.RESULTS: From 2007 to 2010, 64 stageⅠ-Ⅲ colon cancer patients met the eligibility criteria of our study. The mean age of the cohort was 68 years, and 26(41%) patients were male and 38(59%) patients were female. On final pathology, 26 of 64(40.6%) patients had nodepositive(LN+) disease and 38 of 64(59.4%) patients had node-negative(LN-) disease. Outside radiologic review demonstrated sensitivity of 54%(14 of 26 patients) and specificity of 66%(25 of 38 patients) in predicting LN+ disease, whereas secondary radiologist review demonstrated 88%(23 of 26) sensitivity and 58%(22 of 38) specificity. On surgeon review, sensitivity was 69%(18 of 26) with 66% specificity(25 of 38). Secondary radiology review demonstrated the highest accuracy(70%) and the lowest false negative rate(12%), compared to the surgeon review at 67% accuracy and 31% false negative rate and the outside radiology review at 61% accuracy and 46% false negative rate.CONCLUSION: CT LN staging of colon cancer has moderate accuracy, with administration of NCT based on CT potentially resulting in overtreatment. Active search for LN+ may improve sensitivity at the cost of specificity.

Update on the management of sigmoid diverticulitis

Diverticular disease and diverticulitis are the most common non-cancerous pathology of the colon.It has traditionally been considered a disease of the elderly and associated with cultural and dietary habits.There has been a growing evolution in our understanding and the treatment guidelines for this disease.To provide an updated review of the epidemiology,pathogenesis,classification and highlight changes in the medical and surgical management of diverticulitis.Diverticulitis is increasingly being seen in young patients(<50 years).Genetic contributions to diverticulitis may be larger than previously thought.Potential similarities and overlap with inflammatory bowel disease and irritable bowel syndrome exist.Computed tomography imaging represents the standard to classify the severity of diverticulitis.Modifications to the traditional Hinchey classification might serve to better delineate mild and intermediate forms as well as better classify chronic presentations of diverticulitis.Non-operative management is primarily based on antibiotics and supportive measures,but antibiotics may be omitted in mild cases.Interval colonoscopy remains advisable after an acute attack,particularly after a complicated form.Acute surgery is needed for the most severe as well as refractory cases,whereas elective resections are individualized and should be considered for chronic,smoldering,or recurrent forms and respective complications(stricture,fistula,etc.)and for patients with factors highly predictive of recurrent attacks.Diverticulitis is no longer a disease of the elderly.Our evolving understanding of diverticulitis as a clinical entity has led into a more nuanced approach in both the medical and surgical management of this common disease.Non-surgical management remains the appropriate treatment for greater than 70%of patients.In individuals with non-relenting,persistent,or recurrent symptoms and those with complicated disease and sequelae,a segmental colectomy remains the most effective surgical treatment in the acute,chronic,or elective-prophylactic setting.

A Longitudinal Study of Clinical Benefits with Implementation of the Deep Inspiration Breath-Hold Technique in Post-Operative Radiotherapy for Left-Sided Breast Cancer

Purpose/Objectives: We aimed to report clinical effects on critical organ dose and cardiac toxicity from implementation of the deep inspiration breath-hold (DIBH) technique in post-operative extern-beam radiotherapy of patients with left-sided breast cancer, using longitudinal clinical data. Materials/Methods: We retrieved three groups of patients who received post-operative radiotherapy of left-sided breast cancer in our institution in recent years: Groups A and B consist of patients whose treatment did not include internal mammary nodes (IMN) and who were treated with the free breathing technique and with the DIBH technique, respectively, and Group C consists of patients whose radiotherapy included internal mammary nodes with the DIBH technique. Dose parameters for the heart and left lung were retrieved from the treatment plans. Radiation-induced cardiac risks were estimated using existing risk models. Results: The average heart dose was 2.65 ± 0.98 Gy, 1.10 ± 0.29 Gy, and 1.26 ± 0.25 Gy in Groups A, B, and C, respectively. The average heart volumes receiving at least 25 Gy were 7.10 ± 9.79 cc in Group A, 0.07 ± 0.22 cc in Group B, and 0.03 ± 0.08 cc in Group C. On average, the excessive risk of having ischemic heart disease was estimated to be 19.6%, 8.1%, and 9.3% in Groups A, B, and C, respectively. The mean left lung doses were 5.73 ± 1.86 Gy, 5.93 ± 1.55 Gy, and 9.13 ± 1.57 Gy in Groups A, B, and C, respectively. Conclusion: Implementation of the DIBH technique significantly lowered heart dose and decreased the ischemic heart disease risk in patients receiving post-operative radiotherapy for left-sided breast cancer, without significant increase in left lung dose.

Identification of neuron selective androgen receptor inhibitors

AIM To identify neuron-selective androgen receptor(AR) signaling inhibitors, which could be useful in the treatment of spinal and bulbar muscular atrophy(SBMA), or Kennedy's disease, a neuromuscular disorder in which deterioration of motor neurons leads to progressive muscle weakness. METHODS Cell lines representing prostate, kidney, neuron, adipose, and muscle tissue were developed that stably expressed the CFP-AR-YFP FRET reporter. We used these cells to screen a library of small molecules for cell typeselective AR inhibitors. Secondary screening in luciferase assays was used to identify the best cell-type specific AR inhibitors. The mechanism of action of a neuronselective AR inhibitor was examined in vitro using luciferase reporter assays, immunofluorescence microscopy, and immunoprecipitations. Rats were treated with the most potent compound and tissue-selective AR inhibition was examined using RT-q PCR of AR-regulated genes and immunohistochemistry.RESULTS We identified the thiazole class of antibiotics as com-pounds able to inhibit AR signaling in a neuronal cell line but not a muscle cell line. One of these antibiotics, thiostrepton is able to inhibit the activity of both wild type and polyglutamine expanded AR in neuronal GT1-7 cells with nanomolar potency. The thiazole antibiotics are known to inhibit FOXM1 activity and accordingly, a novel FOXM1 inhibitor FDI-6 also inhibited AR activity in a neuron-selective fashion. The selective inhibition of AR is likely indirect as the varied structures of these compounds would not suggest that they are competitive antagonists. Indeed, we found that FOXM1 expression correlates with cell-type selectivity, FOXM1 co-localizes with AR in the nucleus, and that sh RNA-mediated knock down of FOXM1 reduces AR activity and thiostrepton sensitivity in a neuronal cell line. Thiostrepton treatment reduces FOXM1 levels and the nuclear localization of beta-catenin, a known co-activator of both FOXM1 and AR, and reduces the association between beta-catenin and AR. Treatment of rats with thiostrepton demonstrated AR signaling inhibition in neurons, but not muscles. CONCLUSION Our results suggest that thiazole antibiotics, or other inhibitors of the AR-FOXM1 axis, can inhibit AR signaling selectively in motor neurons and may be useful in the treatment or prevention of SBMA symptoms.

New Gene Therapy Strategies for the Deletion of Exon 44 of Dystrophin Gene Based on Gene Editing by TALENs

Duchenne Muscular Dystrophy (DMD) is a severe childhood form of muscular dystrophy. Both the severe form and its milder form of Becker Muscular Dystrophy (BMD) are caused by the mutation of dystrophin gene. Different from some other genetic diseases such as hemophilia that can be treated by replacement therapy, there is no effective therapy for muscular dystrophy in conventional medication. Gene editing technology from the recently developed engineered nucleases such as TALENs has been successfully employed in genome modification of a variety of species, and will be applied in gene therapy of selected human diseases. The genetic basis of DMD and BMD indicates that DMD is a good target for gene therapy through returning the reading frame of dystrophin gene. Gene therapy strategies described here may apply to many other genetic diseases. Wider application of TALENs in gene therapy have the potential to dramatically prolong the lifespan of individuals with genetic diseases.