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Aim: A total of 15–20% of patients with rectal cancer have liver metastases on presentation. The management of these patients is controversial. Heterogeneity in management strategies is considerable, with management often being dependent on local resources and available expertise. Method: Members of the PelvEx Collaborative were invited to participate in the generation of a consensus statement on the optimal management of patients with advanced rectal cancer with liver involvement. Fifteen statements were created for topical discussion on diagnostic and management issues. Panellists were asked to vote on statements and anonymous feedback was given. A collaborative meeting was used to discuss any nuances and clarify any obscurity. Consensus was considered when > 85% agreement on a statement was achieved. Results: A total of 135 participants were involved in the final round of the Delphi questionnaire. Nine of the 15 statements reached consensus regarding the management of patients with advanced rectal cancer and oligometastatic liver disease. Routine use of liver MRI was not recommended for patients with locally advanced rectal cancer, unless there was concern for metastatic disease on initial computed tomography staging scan. Induction chemotherapy was advocated as first-line treatment in those with synchronous liver metastases in locally advanced rectal cancer. In the presence of symptomatic primary disease, a diverting stoma may be required to facilitate induction chemotherapy. Overall, only one-quarter of the panellists would consider simultaneous pelvic exenteration and liver resection. Conclusion: This Delphi process highlights the diverse treatment of advanced rectal cancer with liver metastases and provides recommendations from an experienced international group regarding the multidisciplinary management approach.

Background Perforations are a rare but serious complication of colorectal cancer. The current standard of treatment is emergent surgery followed by adjuvant chemotherapy. The concern with this approach is not only the uncertainty of achieving a R0 resection but also potential injury to adjacent vessels, nerves and ureters due to inflamed tissue planes. A subset of this patient population with a contained perforation who are clinically stable may have superior oncological outcomes with local sepsis control, neoadjuvant therapy followed by radical resection. The aim of this study is to report on the pre-operative safety profile for neoadjuvant therapy in the setting of an abscess from colon cancer perforation and the short-term oncological surgical quality outcomes. Methods In this retrospective observational study, all consecutive perforated colon cancer receiving neoadjuvant therapy from Jan 2010 to Dec 2019 were included. Results There were 21 patients that met the inclusion criteria. The most common symptom at presentation was abdominal pain (71.4%) and most common site of perforation was sigmoid colon (61.9%). Local sepsis control was achieved with a combination of radiological or surgical drainage, diverting ostomy and/or intravenous antibiotics. Thirteen patients had long-course chemoradiation and eight patients had neoadjuvant chemotherapy. Of these, 13 (61.9%) had tumour regression, with one patient having a pathological complete response. All patients achieved a R0 resection. Conclusions In a small subset of patients with colon cancer perforation, this study has demonstrated the potential safe usage of neoadjuvant therapy first before radical surgery to achieve a clear resection margin.

Aim Complete mesocolic excision (CME) with central vascular ligation (CVL) has been advocated for right colon adenocarcinoma (RC), but the radicality of vascular dissection remains controversial. Our aim is to report outcomes of selective CVL (D3 lymphadenectomy) during minimally invasive CME for RC. Method A prospective database identified patients who were treated for RC between 2009 and 2016. Minimally invasive CME was standard. The radicality of lymphadenectomy was defined as high ligation (HL) versus CVL based on operative reports and videos. Two blinded radiologists independently evaluated the pre- and postoperative CT scans for radiographically abnormal nodes. Results Of 197 patients who underwent CME, HL was performed in 56 (28%) and CVL in 141 (72%). There were no baseline differences in age, sex, body mass index, American Society of Anesthesiologists score or pathological staging, and there were no major intra-operative complications in either group (including no major vascular injuries). The median total number of nodes retrieved was 27 and 31 (P = 0.011) in HL and CVL groups, resepctively, with pathologically positive nodes identified in 33.9% and 39.8% (P = 0.704), respectively. Preoperative imaging identified abnormal cN3 nodes in 1.5% of patients; all of whom underwent CVL. No abnormal cN2 or cN3 nodes remained on postoperative imaging. The 60-day mortality was 0.5%, and major morbidity was 4%. One patient (0.5%) had an anastomotic recurrence after a median follow-up of 22 months. Conclusion With imperfect preoperative clinical nodal staging, and in the absence of randomized data, the low morbidity and oncological outcomes observed support the approach of CME with HL as a minimum standard, with CVL (D3 lymphadenectomy) in selected cases.

The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electrophilic quinones. These elusive, highly reactive metabolites may induce liver injury in the case of flupirtine and blue tissue discoloration after prolonged intake of retigabine. We examined which structural features can be altered to avoid the detrimental oxidation of the aromatic ring and shift oxidation toward the formation of more benign metabolites. Structure-activity relationship studies were performed to evaluate the KV 7.2/3 channel opening activity of 45 derivatives. Sulfide analogues were identified that are devoid of the risk of quinone formation, but possess potent KV 7.2/3 opening activity. For example, flupirtine analogue 3-(3,5-difluorophenyl)-N-(6-(isobutylthio)-2-(pyrrolidin-1-yl)pyridin-3-yl)propanamide (48) has 100-fold enhanced activity (EC50 =1.4 nm), a vastly improved toxicity/activity ratio, and the same efficacy as retigabine in vitro.

A series of 2-pyrimidinyl-piperazinyl-alkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5-HT1A , 5-HT7 , and phosphodiesterases PDE4 and PDE10. The most potent compound 2-pyrimidinyl-1-piperazinyl-butyl-imidazo[2,1-f]purine-2,4-dione (4b) behaved as strong and selective antagonist of 5-HT1A . Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands' affinity and potency in the 5-HT1A receptor. Compound 4b in silico models demonstrated drug-likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes system. Experimentally obtained value of apparent permeability coefficient Papp for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant- and anxiolytic-like activities of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first-pass effect.

We report a large cohort of pediatric patients with human monocytic ehrlichiosis (HME), enabling an estimated incidence of secondary hemophagocytic lymphohistiocytosis (HLH) in hospitalized children with HME. Among 49 children with PCR-confirmed Ehrlichia infection, 8 (16%) met current criteria for HLH. Those with HLH had more significant hematologic abnormalities and longer durations from symptom onset to admission and definitive anti-infective therapy. Among these eight, three received chemotherapy plus doxycycline, one of whom died; the other five were treated with doxycycline without chemotherapy, and all survived without HLH recurrence. Our findings demonstrate that antimicrobial therapy alone can successfully resolve Ehrlichia-associated HLH.

BACKGROUND The role of surgical resection in the treatment of patients with metastatic/recurrent gastrointestinal stromal tumors (GIST) is unclear. The aim of this study was to identify preoperative factors associated with oncologic outcomes for recurrent/metastatic GIST after tyrosine kinase inhibitor (TKI) therapy. METHODS We identified 107 patients with metastatic or recurrent GIST treated with TKIs and surgical resection (2002-2012). Patients that underwent palliative or incomplete resection were excluded. Complete resection was achieved in 87 patients which comprise the analytic cohort. Univariate and multivariate analyses were conducted to identify risk factors for GIST-specific survival (DSS) and time-to-recurrence (TTR). RESULTS At a median follow-up of 51 months (91 months for survivors), median DSS was 74 months and TTR was 21 months. By univariate analysis, unifocal disease, duration of TKI

Ultraviolet radiation (UVR) is one of the most important environmental factors involved in photoaging. Exposure to UVR leads to dysregulation of expression of cell cycle-related proteins which play key role in skin photodegradation that pretends to develop carcinogenesis. This study examines the role of various UVB doses on the expression of transforming growth factor beta (TGF-β), Smad2, cathepsin K, progerin and matrix metalloproteinases (MMPs)-1,-3,-8,-9. A group consisting of 63 healthy individuals underwent one of the following treatments: (1) whole body exposed to UVB irradiation on each of 10 consecutive days with 0.7 MED, or (2) whole-body irradiation as described followed by a single erythemal UVB dose on a small body area, or (3) irradiated only with a single erythemal UVB dose on small body area, or (4) were not irradiated at all (control group). When we compared all irradiated groups to the control group, there was significantly higher expression of TGF-β, MMP-1,-3,-9 and cathepsin K proteins evaluated by Western blot method. The results suggest the role of UVB in impairment of proteins expression that is involved in cell cycle's regulation. Changes in the protein expression involved by acute and chronic UVR confirm its essential role in skin photodestruction. Moreover, obtained result indicates the tendency to occurrence of photoadaptation phenomenon.

Background Cobalt chloride (CoCl2 ) is administered to racehorses to enhance performance. The purpose of this study was to evaluate the clinical, cardiovascular, and endocrine effects of parenterally administered CoCl2 . Objectives To describe the effects of weekly intravenous doses of CoCl2 on Standardbred horses. Animals Five, healthy Standardbred mares. Methods Prospective, randomized, experimental dose-escalation pilot. Five Standardbred mares were assigned to receive 1 of 5 doses of CoCl2 (4, 2, 1, 0.5, or 0.25 mg/kg) weekly IV for 5 weeks. Physical examination, blood pressure, cardiac output, and electrocardiography (ECG) were evaluated for 4 hours after administration of the first and fifth doses. Blood and urine samples were collected for evaluation of cobalt concentration, CBC and clinical chemistry, and hormone concentrations. Results All mares displayed pawing, nostril flaring, muscle tremors, and straining after CoCl2 infusion. Mares receiving 4, 2, or 1 mg/kg doses developed tachycardia after dosing (HR 60-126 bpm). Ventricular tachycardia was noted for 10 minutes after administration of the 4 mg/kg dose. Increases in systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP) occurred after administration of all doses (4, 2, 1, 0.5, and 0.25 mg/kg). Profound hypertension was observed after the 4 mg/kg dose (SAP/DAP, MAP [mmHg] = 291-300/163-213, 218-279). Hemodynamics normalized by 1-2 hours after administration. ACTH and cortisol concentrations increased within 30 minutes of administration of all CoCl2 doses, and cardiac troponin I concentration increased after administration of the 4 and 2 mg/kg doses. Conclusions and clinical importance The degree of hypertension and arrhythmia observed after IV CoCl2 administration raises animal welfare and human safety concerns.