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Jiten Desai,1 Mohamed Elnaggar,2 Ahmed A Hanfy,2 Rajkumar Doshi2 1Department of Internal Medicine, Nassau University of Medical Center, East Meadow, NY, USA; 2Department of Internal Medicine, University of Nevada Reno School of Medicine, Reno, NV, USACorrespondence: Rajkumar DoshiDepartment of Internal Medicine, University of Nevada Reno School of Medicine, 1155 Mill St W11, Reno, NV 89502, USATel +1 201 885 8992Email rdoshi@med.unr.eduAbstract: Toxic megacolon (TM) is one of the fatal complications of inflammatory bowel disease (IBD) or any infectious etiology of the colon that is characterized by total or partial nonobstructive colonic dilatation and systemic toxicity. It is associated with high morbidity and mortality, and surgical management is necessary for the majority of the cases. An accurate history and physical examination, plain radiographs of the abdomen, sigmoidoscopy, and, most important of all, awareness of the condition facilitate diagnosis in most cases. Operative intervention is warranted when massive hemorrhage, perforation, or peritonitis complicate the clinical scenario or medical therapy fails to control the disease. We sought to review the management challenges of TM and its possible management strategies in this article.Keywords: toxic megacolon, inflammatory bowel disease, management challenges and solutions for toxic megacolon, Clostridium difficile colitis, nitric oxide synthase

Colorectal cancer; Encorafenib; Quality of life Cáncer colorrectal; Encorafenib; Calidad de vida Càncer colorectal; Encorafenib; Qualitat de vida Background In the BEACON CRC study (NCT02928224), encorafenib plus cetuximab with binimetinib {9.3 versus 5.9 months; hazard ratio (HR) [95% confidence interval (CI)]: 0.60 [0.47-0.75]} or without binimetinib [9.3 versus 5.9 months; HR (95% CI): 0.61 (0.48-0.77)] significantly improved overall survival (OS) compared with the previous standard of care (control) in patients with BRAF V600E metastatic colorectal cancer (mCRC). Quality of life (QoL) was a secondary endpoint, assessed using validated instruments. Patients and methods BEACON CRC was a randomized, open-label, phase III study comparing encorafenib plus cetuximab with or without binimetinib and the investigator’s choice of irinotecan plus cetuximab or FOLFIRI plus cetuximab (chemotherapy control) in patients with previously treated BRAF V600E mCRC. Patient-reported QoL assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC) and Functional Assessment of Cancer Therapy—Colorectal (FACT-C). The primary outcome for these tools was time to definitive 10% deterioration. Results Encorafenib plus cetuximab, both with and without binimetinib, was associated with longer median times to definitive 10% deterioration versus the control group in the EORTC Global Health Status scale [HR (95% CI): 0.65 (0.52-0.80) versus 0.61 (0.49-0.75), respectively] and the FACT-C functional well-being subscale [HR (95% CI): 0.62 (0.50-0.76) versus 0.58 (0.47-0.72), respectively]. Consistent results were observed across all subscales of the EORTC and FACT-C instruments. QoL was generally maintained during treatment for the global EORTC and FACT-C scales. Conclusions In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC. This study was sponsored by Array BioPharma Inc, which was acquired by Pfizer, United States; National Cancer Institute, United States in July 2019. This work was also supported by the Cancer Center Core Grant [grant number P30 CA 008748] to Memorial Sloan-Kettering Cancer Center.

Desai J, Elnaggar M, Hanfy AA, Doshi R. Clin Exp Gastroenterol. 2020;13:203—210. The authors wish to add the following reference to the end of the reference section on page 210. 60. UpToDate Inc. Toxic megacolon. Alphen aan den Rijn: Wolters Kluwer; last updated, 2020. Available from: https://www.uptodate.com/contents/toxic-megacolon. Accessed June 28, 2021. The new reference should have been cited throughout the paper in the following places: Page 205, left column, second paragraph, first sentence, the text should read “A complete colonoscopy is extremely risky in patients with TM because it can cause colonic perforation.60” Page 205, right column, line 6, the text should read “TPN provides no proven clinical benefit in terms of avoiding surgical intervention in patients with colitis due to UC.35,60” Page 205, Glucocorticoids section, third and fourth sentences, the text should read “Dexamethasone, by diminishing the expression of NO synthase, has been reported to decrease the colonic diameter.60 Most providers consider methylprednisolone because of its lower potassium wasting and sodium retaining properties, while others prefer prednisolone as the oral and parenteral doses are the same.60” Page 205, Infliximab or Cyclosporine section, first sentence, the text should read “Patients with IBD-related TM who are refractory to three days of intravenous glucocorticoid therapy should receive either Infliximab or Cyclosporine as the secondline therapy.60” Page 205, Infliximab or Cyclosporine section, last sentence, the text should read “Since these three conditions may not be readily distinguishable during an acute flare-up such as TM, many authors suggest treating all IBD-related TM with the same approach.60” Page 206, C. difficile colitis section, third paragraph, first and second sentences, the text should read “Surgery is indicated in patients with colonic perforation, necrosis, or full-thickness ischemia, intraabdominal hypertension or abdominal compartment syndrome, clinical signs of peritonitis, or worsening abdominal exam despite adequate medical therapy, and end-organ failure.60 Besides, white blood cell count >50,000 cell/mL and serum lactate level of >5 mmol/L are relative indications for surgical intervention.60” Page 207, Pregnant women section, second sentence, the text should read “Patients who are in remission at the conception are likely to remain in remission during pregnancy.60” Page 208, Prognosis section, first paragraph, last sentence, the text should read “Colonic perforation is associated with a significantly worse prognosis, with the mortality rate increased by three- to fivefold.6,8,60” Page 208, Prognosis section, fourth paragraph, first sentence, the text should read “The difference in mortality rates may also be due to the biases of medical or surgical providers.60” Page 208, Prognosis section, fourth paragraph, third sentence, the text should read “Surgical studies reveal up to a 50 percent rate of future surgical intervention, including colectomy in patients with TM who initially responded well to medical treatment alone.55,58,60” The authors acknowledge the missing reference as a source of information for their article and apologise for not including it in the original publication. Read the original article

In this paper, we propose a new easily implementable method for solving a class of semi-infinite programs, where an approximate linear semidefinite program is constructed for the concerned semi-infinite program based on the duality theory of semi-infinite programs and the theory of the trigonometric moments. We obtain a lnK/K-optimal solution for the semi-infinite program, where K is the truncation factor. Moreover, we present some numerical examples to show the efficiency of the new method.

BACKGROUND Multiple arterial grafts may result in longer survival than single arterial grafts after coronary-artery bypass grafting (CABG) surgery. We evaluated the use of bilateral internal-thoracic-artery grafts for CABG. METHODS We randomly assigned patients scheduled for CABG to undergo bilateral or single internal-thoracic-artery grafting. Additional arterial or vein grafts were used as indicated. The primary outcome was death from any cause at 10 years. The composite of death from any cause, myocardial infarction, or stroke was a secondary outcome. RESULTS A total of 1548 patients were randomly assigned to undergo bilateral internal-thoracic-artery grafting (the bilateral-graft group) and 1554 to undergo single internal-thoracic-artery grafting (the single-graft group). In the bilateral-graft group, 13.9% of the patients received only a single internal-thoracic-artery graft, and in the single-graft group, 21.8% of the patients also received a radial-artery graft. Vital status was not known for 2.3% of the patients at 10 years. In the intention-to-treat analysis at 10 years, there were 315 deaths (20.3% of the patients) in the bilateral-graft group and 329 deaths (21.2%) in the single-graft group (hazard ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.12; P=0.62). Regarding the composite outcome of death, myocardial infarction, or stroke, there were 385 patients (24.9%) with an event in the bilateral-graft group and 425 patients (27.3%) with an event in the single-graft group (hazard ratio, 0.90; 95% CI, 0.79 to 1.03). CONCLUSIONS Among patients who were scheduled for CABG and had been randomly assigned to undergo bilateral or single internal-thoracic-artery grafting, there was no significant between-group difference in the rate of death from any cause at 10 years in the intention-to-treat analysis. Further studies are needed to determine whether multiple arterial grafts provide better outcomes than a single internal-thoracic-artery graft. (Funded by the British Heath Foundation and others; Current Controlled Trials number, ISRCTN46552265.)

WOS: 000434263000007, PubMed: 29766772, BACKGROUND Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin. METHODS We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding. RESULTS A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P, BayerBayer AG; Janssen Research and Development, Supported by Bayer and Janssen Research and Development.

International audience; BACKGROUND: Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population. METHODS: In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of

Background: To study Argyrophilic Nucleolar Organizer Regions (AgNOR) count in FNAC lymph node in case of lymphadenopathy & to differentiate between malignant &non-malignant lesions Aim: To prove the diagnostic & Prognostic role of AgNOR in tumour pathology & application of AgNOR techniques to non-neoplastic& neoplastic growth & evaluation of AgNOR in cytology of various lesions of lymph nodes. Materials and Methods: Lymph node FNAC specimens were taken from 150 patients attending pathology department of Shri M.P.Shah Govt. Medical College & GGG hospital, Jamnagar, Gujarat, India during the period of January 2004 to February 2006. FNA of enlarged lymphnode was taken & smears were prepared & fixed in cytofix (50% ethly alcohol) also all smears were stained by H & E(were confirmed) as well as silver nitrate stain. 100 nuclei were assessed for each smear by 100x oil immersion lenses. Result: In this study a total number of 150 cases were included (80 benign & 70 malignant) in various lesions of lymphnode. Conclusion: AgNOR count is directly proportional to the severity of neoplastic lesions which increases with ascending grades of malignancy. Also it is a good technique in cytology.

BACKGROUND: Recently published guidelines on the medical management of renal stone disease did not address relevant topics in the field of idiopathic calcium nephrolithiasis which are important also for clinical research. DESIGN: A steering committee identified 27 questions which were proposed to a faculty of 44 experts in nephrolithiasis and allied fields. A systematic review of the literature was conducted and 5216 potentially relevant articles were selected; from these 407 articles were deemed to provide useful scientific information. The Faculty divided into working groups analysed the relevant literature. Preliminary statements developed by each group were exhaustively discussed in plenary sessions and approved. RESULTS: Statements were developed to inform clinicians on the identification of secondary forms of calcium nephrolithiasis and systemic complications; on the definition of idiopathic calcium nephrolithiasis; on the use of urinary tests of crystallization and of surgical observations during stone treatment in the management of these patients; on the identification of patients warranting preventive measures; on the role of fluid and nutritional measures and of drugs to prevent recurrent episodes of stones; and finally on the cooperation between the urologist and nephrologist in the renal stone patients. CONCLUSIONS: This document has addressed idiopathic calcium nephrolithiasis from the perspective of a disease that can associate with systemic disorders emphasizing the interplay needed between urologists and nephrologists. It is complementary to the American Urological Association and European Association of Urology guidelines. Future areas for research are identified.

Percutaneous nephrolithotomy (PCNL) is considered to be the first line of treatment for large renal stones. Though PCNL comes with higher morbidity, its efficacy is unbeaten by other minimally invasive modalities. However, potential complications, such as bleeding, occur. Improved skills and modifications of the procedure may reduce the probability of adverse outcomes. This article discusses the current trends and standards in PCNL technique with special focus on all important steps as positioning, access, instruments, dilation, disintegration, and exit, including outcomes, complication management, and training modalities. © 2017, Springer-Verlag Berlin Heidelberg.

The relationship between rising body mass index (BMI) and prospective risk of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is virtually absent.Determine the extent of the association between BMI and risk of future NAFLD diagnosis, stratifying by sex and diabetes.Two prospective studies using Humedica and Health Improvement Network (THIN) with 1.54 and 4.96 years of follow-up, respectively.Electronic health record databases.Patients with a recorded BMI measurement between 15 and 60 kg/m(2), and smoking status, and 1 year of active status before baseline BMI. Patients with a diagnosis or history of chronic diseases were excluded.None.Recorded diagnosis of NAFLD/NASH during follow-up (Humedica International Classification of Diseases, Ninth Revision code 571.8, and read codes for NAFLD and NASH in THIN).Hazard ratios (HRs) were calculated across BMI categories using BMI of 20-22.5 kg/m(2) as the reference category, adjusting for age, sex, and smoking status. Risk of recorded NAFLD/NASH increased linearly with BMI and was approximately 5-fold higher in Humedica (HR = 4.78; 95% confidence interval, 4.17-5.47) and 9-fold higher in THIN (HR = 8.93; 7.11-11.23) at a BMI of 30-32.5 kg/m(2) rising to around 10-fold higher in Humedica (HR = 9.80; 8.49-11.32) and 14-fold higher in THIN (HR = 14.32; 11.04-18.57) in the 37.5- to 40-kg/m(2) BMI category. Risk of NAFLD/NASH was approximately 50% higher in men and approximately double in those with diabetes.These data quantify the consistent and strong relationships between BMI and prospectively recorded diagnoses of NAFLD/NASH and emphasize the importance of weight reduction strategies for prevention and management of NAFLD.

Background: “Trapezius squeeze test” (TST) is a simple test to perform in which 1–2 inches of trapezius muscle is held and squeezed in full thickness and response is evaluated in the form of toe/body movement. We compared the effectiveness of the trapezius squeeze test (TST) with the Jaw thrust (JT) as clinical indicators for optimal anaesthesia depth for Proseal laryngeal mask airway (PLMA) insertion in spontaneously breathing children under sevoflurane anaesthesia. Materials and methods: 60 children between 2 to 8 years of age, weighing 10 to 20 kg, of ASA physical status I & II undergoing minor surgical procedures were randomly allocated to the group T (TST, n=30) and the group J (JT, n=30). Anaesthesia was induced using 4% sevoflurane in O2. As the child lost the eyelash reflex, TST or JT was performed in respective group & repeated every 15 sec till it became negative. When it became negative, a well lubricated size 2 P LMA was inserted. Insertion time of PLMA; end-tidal and MAC value of sevoflurane at the time of PLMA insertion; ease of PLMA insertion and complications as well as hemodynamic parameters were recorded. Results: In Group T, Mean time for TST to become negative was 4.48 ± 0.6 minutes and insertion condition was excellent in 30 patients (100%) compared to 4.85 ± 0.71 minutes and excellent condition in 27 patients (90%) in group J. In group T, PLMA was successfully inserted in 1st attempt in 100 % while in 97% in group J. coughing was observed in 2 patients in group J.

OBJECTIVES: Microsatellite instability (MSI) is an established marker of good prognosis in colorectal cancer (CRC). Chromosomal instability (CIN) is strongly negatively associated with MSI and has been shown to be a marker of poor prognosis in a small number of studies. However, a substantial group of "double-negative" (MSI-/CIN-) CRCs exists. The prognosis of these patients is unclear. Furthermore, MSI and CIN are each associated with specific molecular changes, such as mutations in KRAS and BRAF, that have been associated with prognosis. It is not known which of MSI, CIN, and the specific gene mutations are primary predictors of survival. METHODS: We evaluated the prognostic value (disease-free survival, DFS) of CIN, MSI, mutations in KRAS, NRAS, BRAF, PIK3CA, FBXW7, and TP53, and chromosome 18q loss-of-heterozygosity (LOH) in 822 patients from the VICTOR trial of stage II/III CRC. We followed up promising associations in an Australian community-based cohort (N=375). RESULTS: In the VICTOR patients, no specific mutation was associated with DFS, but individually MSI and CIN showed significant associations after adjusting for stage, age, gender, tumor location, and therapy. A combined analysis of the VICTOR and community-based cohorts showed that MSI and CIN were independent predictors of DFS (for MSI, hazard ratio (HR)=0.58, 95% confidence interval (CI) 0.36-0.93, and P=0.021; for CIN, HR=1.54, 95% CI 1.14-2.08, and P=0.005), and joint CIN/MSI testing significantly improved the prognostic prediction of MSI alone (P=0.028). Higher levels of CIN were monotonically associated with progressively poorer DFS, and a semi-quantitative measure of CIN was a better predictor of outcome than a simple CIN+/- variable. All measures of CIN predicted DFS better than the recently described Watanabe LOH ratio. CONCLUSIONS: MSI and CIN are independent predictors of DFS for stage II/III CRC. Prognostic molecular tests for CRC relapse should currently use MSI and a quantitative measure of CIN rather than specific gene mutations.

Objective. This study was a prospective cross-sectional clinical audit of patients with mandibular fractures at the Charlotte Maxeke Johannesburg Academic Hospital. Methods. Between 1 March and 31 August 2004, patients with mandibular fractures seen by one clinician had their details recorded. Results. The female:male ratio of the study sample of 133 patients was 1:6. Seventy-seven per cent were aged 20 - 39 years. Most fractures (86%) were the result of interpersonal violence, and 65% were alcohol-associated. Open reduction (75%) was the most common treatment. Conclusion. This study had the highest interpersonal violence and open reduction rates of all the studies reviewed.

Jaw bones are rarely involved in secondary hyperparathyroidism. We report a case of 13 year old girl who presented with progressive chronic renal failure and secondary hyperparathyroidism. Five months after beginning of hemodialysis, a large brown tumor developed on the hard palate, extending to the maxilla causing difficulty in swallowing and breathing. She died of massive intestinal hemorrhage five months after excision of the mass.

Between 1981 and 1987, 11 patients underwent oesophageal resection following endoscopic perforation of the oesophagus. They had a median age of 67 years with a range of 36 to 88 years. They all were managed either by one- or two-stage oesophageal resections. Six patients were perforated at other hospitals, 5 on site. Seven had carcinoma of the middle or lower third of the oesophagus, 2 of these were perforated at attempted palliative intubation. Four had benign peptic strictures perforated during dilatation. Seven were resected within the first 24 hours and 4 between 2 and 10 days after perforation. All 4 patients with benign disease survived but 4 of the 7 patients with cancer died giving an operative mortality of 36.3%. Respiratory complications were the most common postoperative problem: all deaths were attributed to respiratory failure. Perforation of the thoracic oesophagus carries a high mortality. Resection after perforation in benign strictures may be life saving in a potentially lethal condition but resection after perforation, even in operable cancer, still carries a high mortality.

Operative mortality and morbidity following oesophageal resection has fallen in recent years. We have attempted to identify the factors responsible for this improvement by reviewing the results of surgery at this hospital over the last 6 years. Two hundred and two oesophageal resections were performed between January 1981 and June 1987 for carcinoma. Of these, 21 patients (10.4%) died before leaving hospital. Fourteen patients died of multisystem failure, 1 died of pure respiratory failure and 2 died of renal failure. Two died of surgical causes (other than anastomotic leak), 1 died of pulmonary embolus and 1 from a cerebro-vascular accident. No patient died of purely cardiac causes. The most significant risk factors in those dying (Chi-square test) were: postoperative respiratory failure, defined as reventilation after initial successful extubation, (P less than or equal to 0.001), reoperation as an emergency in the early postoperative period (P less than or equal to 0.001), anastomotic leak (P less than or equal to 0.01) and age over 70 (P less than or equal to 0.005). Less significant risk factors were chyle leak and histologically undifferentiated tumour. Of the 181 survivors, 103 left hospital with no complications of any kind. The mean stay in hospital for survivors was 15 days. Respiratory infection occurred in 22% of patients, prolonged gastric stasis in 8%, wound infection in 5% and empyema in 1%. As long as high risk groups are accepted for radical surgery, operation will carry a significant mortality in those groups. In others, we believe that perioperative monitoring and early aggressive treatment of complications can further reduce mortality and morbidity.

Colorectal cancer is the second leading cause of cancer deaths worldwide, with a 5-year relative survival of 14% in patients with metastatic colorectal cancer (mCRC). Patients with BRAF V600E mutations, which occur in ∼10%-15% of patients with mCRC, have a poorer prognosis compared with those with wild-type BRAF tumours. The combination of the BRAF inhibitor encorafenib with the epidermal growth factor receptor inhibitor cetuximab currently represents the only chemotherapy-free targeted therapy approved in the USA and Europe for previously treated patients with BRAF V600E-mutated mCRC. As a class, BRAF inhibitors are associated with dermatologic, gastrointestinal, and renal events, as well as pyrexia and secondary skin malignancies. Adverse event (AE) profiles of specific BRAF inhibitors vary, however, and are affected by the specific agents given in combination. In patients with mCRC, commonly reported AEs of cetuximab monotherapy include infusion reactions and dermatologic toxicities. Data from the phase III BEACON CRC study indicate that the combination of encorafenib with cetuximab has a distinct safety profile. Here we review the most frequently reported AEs that occurred with this combination in BEACON CRC and best practices for managing and mitigating AEs that require more than standard supportive care., Highlights • Encorafenib + cetuximab has a distinct safety profile in patients with BRAF V600E-mutated metastatic colorectal cancer. • Effective management strategies can mitigate the impact of AEs, prolonging treatment duration and benefits. • We provide guidance on managing gastrointestinal, skin, and renal AEs. • Specific guidance is given for the management of arthralgia, myalgia, fatigue, asthenia, headache, and pyrexia.

PURPOSE BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAFV600E–mutant metastatic colorectal cancer (mCRC), after progression on 1-2 prior regimens. In the previously reported primary analysis, encorafenib, binimetinib plus cetuximab (ENCO/BINI/CETUX; triplet) and encorafenib plus cetuximab (ENCO/CETUX; doublet) regimens improved overall survival (OS) and objective response rate (ORR; by blinded central review) versus standard of care. The purpose of this analysis was to report updated efficacy and safety data. METHODS In this open-label, phase III trial, 665 patients with BRAF V600E–mutant mCRC were randomly assigned 1:1:1 to receive triplet, doublet, or control. Primary end points were OS and independently reviewed ORR comparing triplet to control. OS for doublet versus control was a key secondary end point. Updated analyses include 6 months of additional follow-up and ORR for all randomized patients. RESULTS Patients received triplet (n = 224), doublet (n = 220), or control (n = 221). Median OS was 9.3 months (95% CI, 8.2 to 10.8) for triplet and 5.9 months (95% CI, 5.1 to 7.1) for control (hazard ratio [HR], 0.60 [95% CI, 0.47 to 0.75]). Median OS for doublet was 9.3 months (95% CI, 8.0 to 11.3) (HR v control, 0.61 [95% CI, 0.48 to 0.77]). Confirmed ORR was 26.8% (95% CI, 21.1% to 33.1%) for triplet, 19.5% (95% CI, 14.5% to 25.4%) for doublet, and 1.8% (95% CI, 0.5% to 4.6%) for control. Adverse events were consistent with the prior primary analysis, with grade ≥ 3 adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet, and control, respectively. CONCLUSION In the BEACON CRC study, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients in the metastatic setting compared with standard chemotherapy. Based on the primary and updated analyses, encorafenib plus cetuximab is a new standard care regimen for previously treated patients with BRAF V600E mCRC.

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.

Background Patients with metastatic colorectal cancer whose disease has progressed on oxaliplatin- and irinotecan-containing regimens may benefit from EGFR-inhibiting monoclonal antibodies if they do not contain mutations in the KRAS gene (are “wild type”). It is unknown whether these antibodies, such as cetuximab, are more efficacious in refractory metastatic colorectal cancer as monotherapy, or in combination with irinotecan. Lack of mutation in KRAS, BRAF and PIK3CA predicts response to EFGR-inhibitors. The ICECREAM trial examines the question of monotherapy versus combination with chemotherapy in two groups of patients: those with a “quadruple wild type” tumour genotype (no mutations in KRAS, NRAS, PI3KCA or BRAF genes) and those with the specific KRAS mutation in codon G13D, for whom possibly EGFR-inhibitor efficacy may be equivalent. Methods and design ICECREAM is a randomised, phase II, open-label, controlled trial comparing the efficacy of cetuximab alone or with irinotecan in patients with “quadruple wild type” or G13D-mutated metastatic colorectal cancer, whose disease has progressed on, or who are intolerant of oxaliplatin- and fluoropyrimidine-based chemotherapy. The primary endpoint is the 6-month progression-free survival benefit of the treatment regimen. Secondary endpoints are response rate, overall survival, and quality of life. The tertiary endpoint is prediction of outcome with further biological markers. International collaboration has facilitated recruitment in this prospective trial of treatment in these infrequently found molecular subsets of colorectal cancer. Discussion This unique trial will yield prospective information on the efficacy of cetuximab and whether this is further enhanced with chemotherapy in two distinct populations of patients with metastatic colorectal cancer: the “quadruple wild type”, which may ‘superselect’ for tumours sensitive to EGFR-inhibition, and the rare KRAS G13D mutated tumours, which are also postulated to be sensitive to the drug. The focus on establishing both positive and negative predictive factors for the response to targeted therapy is an attempt to improve outcomes, reduce toxicity and contain treatment costs. Tissue and blood will yield a resource for molecular studies. Recruitment, particularly of patients with the rare G13D mutation, will demonstrate the ability for international collaboration to run prospective trials in small colorectal cancer molecular subgroups. Trial registration Australian and New Zealand Clinical Trials Registry: ACTRN12612000901808, registered 16 August 2012.

Purpose RAS mutations predict lack of response to epidermal growth factor receptor monoclonal antibody therapy in patients with metastatic colorectal cancer (mCRC), but preclinical studies and retrospective clinical data suggest that patients with tumors harboring the exon 2 KRAS G13D mutation may benefit from cetuximab. We aimed to assess cetuximab monotherapy and cetuximab plus irinotecan in patients with molecularly selected (G13D mutation) chemotherapy-refractory mCRC in a randomized phase II trial of this rare molecular subtype. Patients and Methods Patients with chemotherapy-refractory KRAS G13D mutation–positive mCRC who had progressed within 6 months of irinotecan therapy were randomly assigned to cetuximab 400 mg/m2 loading dose and then 250 mg/m2 once per week with or without irinotecan 180 mg/m2 once every 2 weeks. The primary end point was 6-month progression-free survival; secondary end points were response rate, overall survival, quality of life, and toxicity. Results Fifty-one of 53 patients recruited over 2 years were eligible. The 6-month progression-free survival rate was 10% (95% CI, 2% to 26%) for cetuximab versus 23% (95% CI, 9% to 40%) for cetuximab plus irinotecan with a hazard ratio of 0.74 (95% CI, 0.42 to 1.32). Response and stable disease rates were 0% and 58% for monotherapy versus 9% and 70% for combination treatment, respectively. Overall survival and quality of life were similar; toxicities were higher with combination therapy. Conclusion In patients with G13D-mutated chemotherapy-refractory mCRC, there was no statistically significant improvement in disease control at 6 months with either cetuximab monotherapy or cetuximab plus irinotecan. No responses were seen with single-agent cetuximab. The responses observed with the combination of cetuximab and irinotecan may reflect true drug synergy or persistent irinotecan sensitivity. The ICECREAM (Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation Among Patients with a G13D Mutation) study demonstrates the need to prospectively evaluate hypotheses that were previously supported by retrospective analyses and exemplifies the value of international collaboration in trials of rare molecular subtypes.

Experiments are carried out with a cm-scale bio-mimetic swimming robot, which consists of a body and a rigid helical tail and mimics typical eukaryotic micro organisms, inside circular channels filled with viscous fluids. The body of the robot is made of a cylindrical capsule, which includes an onboard power supply, a dedicated DC-motor, and a driving circuitry with IR-receiver for remote control purposes. In experiments geometric parameters of the helical tail, wavelength and amplitude, and the diameter of the circular channels are varied to understand the effect of those parameters on the swimming speed of the robots. Models, based on slender body theory (SBT) and resistive force theory (RFT), are implemented to predict the swimming speeds, which are then compared with experimentally measured values. A simple model for the DC-motor dynamics is included to account for the contact friction effects on the body rotation rates. Model results agree reasonably well with experimental measurements.

In this paper we investigate the employment of different data reduction techniques to minimize V2I communication in an Intelligent Transportation System (ITS). We consider the context of the PEGASUS Project, where vehicles are equipped with sensor-based devices able to compute and communicate to a Control Centre (CC) information like vehicleaAZs position and speed. The CC relies on a general-purpose data management module that supports the execution of continuous queries as well as standard SQL one-time queries on the collected data to provide various infomobility services.The paper explores two categories of data reduction techniques: independent techniques, where vehicles autonomously send data to the CC, and information-need techniques, where data is sent by taking into account additional data received from the CC. The paper discusses and implements the technical changes needed in the CC to support the required infomobility services under the reduced availability of data. All the investigated techniques have been extensively evaluated in a variety of traffic scenarios.