Immunotherapy in Stage III-IV Colon Cancer: A Propensity Score-Matched Analysis of the National Cancer Database.

SUMMARY: Immunotherapy for the systemic treatment of cancer offers new treatment possibilities for advanced malignancies. Despite promising initial results, evidence on efficacy of immunotherapy for colon cancer is lacking. Thus, we aimed to assess short-term and long-term outcomes of immunotherapy in patients with advanced colon cancer. A US National Cancer Database was searched for patients with stage III-IV colonic adenocarcinoma between 2010 and 2019. Propensity score matching was used to classify the cohort into 2 groups: patients who received immunotherapy and controls. Main outcome measures were primary outcome was overall survival (OS). A total of 23,778 patients with stage III-IV colonic adenocarcinoma were treated with immunotherapy during the study period compared to 114,753 controls. Immunotherapy treated patients were younger (median age 61 vs. 67 y; P<0.001), more often male (57.3% vs. 50.7%, P<0.001), had more private insurance (44.1% vs. 33.7%; P<0.001), had more left-sided tumors (49.5% vs. 39.1%; P<0.001) and liver metastasis (80.2% vs. 61.7%; P<0.001) than controls. Immunotherapy patients received more standard chemotherapy (49.8% vs. 41.6%; P<0.001). After propensity-score matching, mean OS was significantly shorter in the immunotherapy group compared with controls (34.7 vs. 36.2 mo; P=0.008). Cox regression analysis demonstrated that immunotherapy was associated with increased risk for mortality (HR: 1.1; 95% CI: 1.02-1.18; P=0.005). Patients who received immunotherapy had lower 90-day mortality rates compared with controls (2.3% vs. 3.6%; P=0.004), but the groups had equivalent 30-day mortality rates (0.7% vs. 0.8%; P=0.76). Immunotherapy showed no improvement in OS in patients with stage III-IV colon cancer.

Liver Venous Deprivation for Rapid Liver Hypertrophy Before Major Hepatectomy: A Case Report.

Liver venous deprivation (LVD) is an emerging, minimally invasive strategy to induce rapid liver hypertrophy of the future liver remnant (FLR) before a major hepatectomy. LVD (aka "double vein embolization") entails same-session percutaneous embolization of the portal and hepatic veins of the planned liver resection. This report discusses LVD's utilization and technical challenges in managing a 49-year-old male with recurrent multifocal colorectal liver metastases (CRLM). The patient initially underwent neoadjuvant FOLFOX chemotherapy followed by a simultaneous laparoscopic sigmoid colectomy and liver surgery (microwave ablation of segment V and wedge resections of segment one and IVb), followed by completion of chemotherapy. The patient had an R0 resection with clear colon and liver surgical margins. Nine months after the initial surgery, the patient had a rise in tumor markers, and surveillance imaging demonstrated recurrence of liver metastases in segments I and V. LVD was performed by interventional radiology, which led to a 28% increase in FLR (segments II, III, and IV); initially measuring 464 cm3 before LVD and measuring 594 cm3 on post-procedure day 21. The patient underwent right hemi-hepatectomy and caudate resection on post-procedure day 29. The patient did not have any complications and was discharged on postoperative day 6. The patient remains disease-free with no evidence of recurrence at 12 months follow-up.

Genomic Predictors Associated With Exceptional Response to Systemic Therapy in Advanced Pancreatic Cancer.

INTRODUCTION: Exceptional response to therapy is rare in patients with advanced pancreatic cancer. This study explored potential genomic differences between typical and exceptional responses that could confer more favorable biology. METHODS: We included exceptional responders and controls with advanced pancreatic cancer from Cleveland Clinic from April 2013 to August 2017. Exceptional responders were defined as patients with an overall survival of more than 18 months for metastatic disease and more than 24 months for locally advanced disease. Clinical data were obtained, and next-generation sequencing was performed. Statistical analyses comparing the 2 groups were performed using descriptive statistics, the Kaplan-Meier method, and the log-rank test. RESULTS: The study comprised 4 exceptional responders and 6 controls. Both groups were well balanced in age, sex, race, and treatment regimens. Exceptional responders had significantly fewer nonsynonymous mutations than controls (2.25 vs 5.17; P = .014). A mutation count of less than 3 was associated with significantly better progression-free survival (17.2 vs 2.3 months; P = .002) and overall survival (29.4 vs 4.6 months; P = .013). Tumor mutational burden did not differ between exceptional responders and controls (4.88 vs 5.70 mut/Mb; P = .39). CONCLUSION: A lower number of nonsynonymous mutations may correlate with exceptional outcomes in patients with pancreatic cancer. These findings should encourage future studies into genomic signatures of exceptional response.

Immunotherapy in rectal cancer patients-a propensity score matched analysis of the National Cancer Database.

BACKGROUND: Rectal cancer patients with microsatellite instability (MSI-H) are candidates for immunotherapy. However, there is little evidence on its effect on overall survival (OS). METHODS: Retrospective analysis of stage II-IV rectal adenocarcinoma patients in the National Cancer Database (NCDB) between 2010 and 2019. Propensity score matching was adjusted for baseline and treatment confounders. The cohort was divided into patients who received immunotherapy and matched controls. The primary outcome was OS. RESULTS: 5175/206,615 (2.5%) patients with rectal adenocarcinoma underwent immunotherapy. These patients were younger (58 vs 62 years; p < 0.001), more often male (64.4% vs 61.7%; p < 0.001), were more likely to have private insurance (50.8% vs 43.4%; p < 0.001), more metastatic disease at presentation (clinical TNM stage IV-80.8% vs 23.3%; p < 0.001), presented with larger tumors (median: 5 cm vs. 4.2 cm; p < 0.001) and less often underwent surgery (33.7% vs. 69.9%; p < 0.001), radiation therapy (21.5% vs 57.4%; p < 0.001), and standard chemotherapy (38.1% vs 61%; p < 0.001) than controls. After matching, 488 patients were in each group. OS was significantly shorter in the immunotherapy group (mean survival: 56.4 months (95% CI: -53.03-59.86)) compared to controls (mean survival: 70.5 months (95% CI: -66.15-74.92) (p = 0.004)). Cox regression analysis of factors associated with OS demonstrated that immunotherapy was associated with increased mortality (HR 2.16; 95% CI: 2.09-2.24; p < 0.001). After clinical staging stratification, immunotherapy was associated with improved OS in stage IV (HR 0.91, 95% CI: 0.88-0.95; p < 0.001) but lower survival in stage II (HR 2.38; 95% CI: 2.05-2.77; p < 0.001) and stage III (HR 2.43; 95% CI: 2.18-2.7; p < 0.001) patients. CONCLUSION: Immunotherapy showed modest increase in OS in stage IV metastatic rectal cancer. OS was significantly lower in stage II-III disease treated with immunotherapy.

Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline.

PURPOSE: To develop recommendations involving targeted therapies for patients with advanced gastroesophageal cancer. METHODS: The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS: Eighteen randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS: For human epidermal growth factor receptor 2 (HER2)-negative patients with gastric adenocarcinoma (AC) and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5, first-line therapy with nivolumab and chemotherapy (CT) is recommended. For HER2-negative patients with esophageal or gastroesophageal junction (GEJ) AC and PD-L1 CPS ≥ 5, first-line therapy with nivolumab and CT is recommended. First-line therapy with pembrolizumab and CT is recommended for HER2-negative patients with esophageal or GEJ AC and PD-L1 CPS ≥ 10. For patients with esophageal squamous cell carcinoma and PD-L1 tumor proportion score ≥ 1%, nivolumab plus CT, or nivolumab plus ipilimumab is recommended; for patients with esophageal squamous cell carcinoma and PD-L1 CPS ≥ 10, pembrolizumab plus CT is recommended. For patients with HER2-positive gastric or GEJ previously untreated, unresectable or metastatic AC, trastuzumab plus pembrolizumab is recommended, in combination with CT. For patients with advanced gastroesophageal or GEJ AC whose disease has progressed after first-line therapy, ramucirumab plus paclitaxel is recommended. For HER2-positive patients with gastric or GEJ AC who have progressed after first-line therapy, trastuzumab deruxtecan is recommended. In all cases, participation in a clinical trial is recommended as it is the panel's expectation that targeted treatment options for gastroesophageal cancer will continue to evolve.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

The Gut Microbiome and Alzheimer's Disease: A Growing Relationship.

Evidence that the gut microbiota plays a key role in the pathogenesis of Alzheimer's disease is already un-ravelling. The microbiota-gut-brain axis is a bidirectional communication system that is not fully understood but includes neural, immune, endocrine, and metabolic pathways. The progression of Alzheimer's disease is supported by mechanisms related to the imbalance in the gut microbiota and the development of amyloid plaques in the brain, which are at the origin of Alzheimer's disease. Alterations in the composition of the gut microbiome led to dysregulation in the pathways governing this system. This leads to neurodegeneration through neuroinflammation and neurotransmitter dysregulation. Neurodegeneration and disruption of the blood-brain barrier are frontiers at the origin of Alzheimer's disease. Furthermore, bacteria populating the gut microbiota can secrete large amounts of amyloid proteins and lipopolysaccharides, which modulate signaling pathways and alter the production of proinflammatory cytokines associated with the pathogenesis of Alz-heimer's disease. Importantly, through molecular mimicry, bacterial amyloids may elicit cross-seeding of misfolding and induce microglial priming at different levels of the brain-gut-microbiota axis. The potential mechanisms of amyloid spreading include neuron-to-neuron or distal neuron spreading, direct blood-brain barrier crossing, or via other cells such as astrocytes, fibroblasts, microglia, and immune system cells. Gut microbiota metabolites, including short-chain fatty acids, pro-inflammatory factors, and neurotransmitters may also affect AD pathogenesis and associated cognitive decline. The purpose of this review is to summarize and discuss the current findings that may elucidate the role of gut microbiota in the development of Alzheimer's disease. Understanding the underlying mechanisms may provide new insights into novel therapeutic strategies for Alzheimer's disease, such as probiotics and targeted oligosaccharides.

Medullary carcinoma of the colon: A comprehensive analysis of the National Cancer Database.

PURPOSE: Medullary carcinomas (MC) of the colon are uncommon tumors. In this study, we analyzed demographic and disease characteristics as well as survival outcomes of MC versus undifferentiated (UDA) and poorly differentiated (PDA) adenocarcinomas (AC) of the colon. MATERIALS AND METHODS: The National Cancer Database (2004-2018) was utilized to identify patients with colon cancer. Patient demographics (including age, gender, race), disease characteristics (including grade, TNM stage, carcinoembryonic levels, perineural and lymphovascular invasion, lymph node status, microsatellite stability, KRAS mutation, and primary tumor site), and facility type and location were evaluated. Chi-square tests were used to compare descriptive data. Cox Regression and Kaplan Meier analyses were used to analyze survival characteristics. RESULTS: 1,041,753 patients with colon cancer were identified of whom 2709 patients had MC and 897,902 had AC (136,597 PDA and 18,042 UDA). MC was seen in older patients (mean age 74 ± 13 years) and women (72.5% vs. 27.5% males). Most MCs were poorly differentiated (63.3%), and 82.4% of patients with MC had microsatellite instability. Fewer patients with MC had perineural invasion (15.6% vs. 22.0% in PDA and 22.4% in UDA, p < 0.001) and positive lymph nodes (38.4% versus 59.9% with PDA and 59.7% with UDA, p < 0.0001). MC diagnosis increased by year (Cochran-Armitage trend test, p < 0.0001). Kaplan Meir analysis revealed a better prognosis for patients with MC when compared to PDA or UDA (p < 0.001). CONCLUSION: Given the rarity, pathologists should maintain a high suspicion for MC when encountering poorly differentiated or undifferentiated right-sided colon cancer with associated MSI-H.

Total Neoadjuvant Therapy Is a Predictor for Complete Pathological Response in Patients Undergoing Surgery for Rectal Cancer.

INTRODUCTION: Total neoadjuvant therapy (TNT) is a new therapeutic strategy in patients with rectal cancer. We examined the role of TNT, in addition to other pre-operative factors, as a predictor for pathologic complete response (pCR). METHODS: A retrospective analysis of all rectal cancer patients who underwent surgery between 2016 and 2021 was conducted. Patients were classified into two groups-pCR group and residual tumor group. Patient data were reviewed and entered into univariate and multivariate analyses to determine predictors of pCR. RESULTS: A total of 172 patients were treated with neoadjuvant therapy and underwent surgery during the study period. Sixty patients (34.9%) were treated with TNT while 112 (65.1%) were treated with traditional neoadjuvant chemoradiation. The overall pCR rate was 25.6% (44 patients), with 31.6% (19 patients) in patients who received TNT compared to 22.3% (25 patients) in patients who received neoadjuvant chemoradiation (NCRT). Univariate analysis of clinical and radiological factors correlated with pCR demonstrated no significant differences between the two groups in cT stage (p = 0.46), cN stage (p = 0.52), positive circumferential resection margin (CRM) (p = 0.72), tumor location (p = 0.35), symptomatic presentation (p = 0.09), and anal sphincter involvement (p = 0.68). Multivariate logistic analysis demonstrated that only pre-operative TNT (OR:2.35; 95% CI 1.06-5.25; p = 0.03) was predictive of pCR, while extramural vascular invasion (EMVI) was a predictor for lower rates of pCR (OR: 0.28; 95% CI 0.09-0.9; p = 0.03). CONCLUSION: Rectal cancer patients undergoing TNT prior to surgery have a higher chance of developing a complete pathologic response. Evaluation of this therapy should be continued and extended to larger numbers of patients to see if the differences we observed are real.

Assessment of mesorectal fascia status in MRI compared with circumferential resection margin after total mesorectal excision and predictors of involved margins.

BACKGROUND: Circumferential resection margin is an important prognosticator for total mesorectal excision outcome. We investigated the status of mesorectal fascia on magnetic resonance imaging compared with circumferential resection margin on pathology and factors associated with status change. METHODS: This was a retrospective analysis of a prospective database of rectal cancer patients who underwent surgery. Mesorectal fascia status on magnetic resonance imaging done before neoadjuvant therapy and circumferential resection margin status on pathology were compared. The study outcomes were factors associated with a margin status conversion between magnetic resonance imaging and pathology, and predictors of involved circumferential resection margin. RESULTS: In total, 244 patients (average follow-up of 25.4 months) were included. Eighty-one (33.2%) patients had potentially involved mesorectal fascia in magnetic resonance imaging and 12 (4.9%) had involved circumferential resection margin in pathology. A total of 2.8% of patients had a conversion of clear mesorectal fascia in magnetic resonance imaging to involved circumferential resection margin. Abdominoperineal resection was significantly associated with this status change (odds ratio: 25, 95% confidence interval: 2.4-255.8, P = .007). In total, 7.4% of patients with potentially involved mesorectal fascia had persistently involved circumferential resection margin. Lack of total neoadjuvant therapy was associated with higher, yet statistically insignificant, odds of persistently involved circumferential resection margin (odds ratio: 12, 95% confidence interval: 0.65-220.8, P = .09). The significant independent predictors of involved circumferential resection margin were body mass index (odds ratio: 1.2, P = .016) and abdominoperineal resection (odds ratio: 4.22, P = .04). CONCLUSION: Change of clear mesorectal fascia in magnetic resonance imaging to an involved circumferential resection margin in pathology was recorded in 2.8% of patients; abdominoperineal resection might be associated with this change. Approximately 7% of patients had persistent involvement of circumferential resection margin as determined by pathology. Omission of total neoadjuvant therapy might be associated with persistent margin involvement.

The Urogenital System's Role in Diseases: A Synopsis.

The human microbiota contains ten times more microbial cells than human cells contained by the human body, constituting a larger genetic material than the human genome itself. Emerging studies have shown that these microorganisms represent a critical determinant in human health and disease, and the use of probiotic products as potential therapeutic interventions to modulate homeostasis and treat disease is being explored. The gut is a niche for the largest proportion of the human microbiota with myriad studies suggesting a strong link between the gut microbiota composition and disease development throughout the body. More specifically, there is mounting evidence on the relevance of gut microbiota dysbiosis in the development of urinary tract disease including urinary tract infections (UTIs), chronic kidney disease, and kidney stones. Fewer emerging reports, however, are suggesting that the urinary tract, which has long been considered 'sterile', also houses its unique microbiota that might have an important role in urologic health and disease. The implications of this new paradigm could potentially change the therapeutic perspective in urological disease.

Total neoadjuvant therapy: Fact, fantasy, or fallacy?

Colorectal cancer is the second leading cause of cancer death in the United States for men and women, with an estimated 146,000 new cases per year - a staggering 53,000 patients die each year. Rectal cancer comprises a third of these patients, with a 5-year survival rate of 67%. Management of locally advanced rectal cancer in the U.S. had remained stagnant for more than a decade, with most of these patients being treated with long-course chemoradiotherapy, surgery, followed by adjuvant chemotherapy; adjuvant chemotherapy being administered despite lacking a high level of evidence. Over the past few years, with rectal cancer death rates exceeding 30% from metastatic disease, growing interest focused on the attributes of induction chemotherapy to eradicate minimal residual disease and purportedly increase survival. This led to the development of total neoadjuvant therapy (TNT). We now have high-quality data from randomized prospective trials to review the facts, fantasies, and fallacies of TNT.

Further structural characterization of ovine forestomach matrix and multi-layered extracellular matrix composites for soft tissue repair.

Decellularized extracellular matrix (dECM)-based biomaterials are of great clinical utility in soft tissue repair applications due to their regenerative properties. Multi-layered dECM devices have been developed for clinical indications where additional thickness and biomechanical performance are required. However, traditional approaches to the fabrication of multi-layered dECM devices introduce additional laminating materials or chemical modifications of the dECM that may impair the biological functionality of the material. Using an established dECM biomaterial, ovine forestomach matrix, a novel method for the fabrication of multi-layered dECM constructs has been developed, where layers are bonded via a physical interlocking process without the need for additional bonding materials or detrimental chemical modification of the dECM. The versatility of the interlocking process has been demonstrated by incorporating a layer of hyaluronic acid to create a composite material with additional biological functionality. Interlocked composite devices including hyaluronic acid showed improved in vitro bioactivity and moisture retention properties.

Can normalized carcinoembryonic antigen following neoadjuvant chemoradiation predict tumour recurrence after curative resection for locally advanced rectal cancer?

AIM: The aim of this work was to evaluate whether normalized carcinoembryonic antigen (CEA) following neoadjuvant chemoradiation predicts the prognosis following curative resection in locally advanced rectal cancer. METHOD: Patients who underwent neoadjuvant chemoradiation and curative resection for locally advanced rectal cancer between 2010 and 2015 were divided into three groups: Group A (n = 119, normal-to-normal): normal CEA before and after neoadjuvant chemoradiation; Group B (n = 37, high-to-normal): elevated CEA before and normal CEA after neoadjuvant chemoradiation; Group C (n = 36, high-to-high): elevated CEA before and after neoadjuvant chemoradiation. Overall and disease-free survival were compared. Univariate and multivariate analyses identified potential predictors for recurrence. RESULTS: One hundred and ninety two patients [median age 59 years (range 31-87), 65.1% male] were identified: 54.7% had low rectal cancer: 12.5% were clinical stage T4 and 70.3% were clinically node positive; 21.9% achieved complete pathological response; 24.5% had abdominoperineal resection (APR); and 70.3% underwent adjuvant chemotherapy following curative resection. Significantly more patients in Group C underwent APR (p = 0.0209), had advanced pathological T stage (P = 0.0065) and a higher prevalence of perineural invasion (p = 0.0042). Overall and disease-free survival were significantly higher for Group A than for Group C [hazard ratio (HR) = 4.32, 95% CI = 1.66-11.21, p = 0.0026 and HR=2.68, 95% CI = 1.33-5.40, p = 0.0057, respectively]. No significant difference was noted between Groups A and B for overall (p = 0.0591) or disease-free (p = 0.2834) survival. Another risk factor associated with recurrence and death was clinical T4 stage; nodal positivity was a risk factor only for recurrence. CONCLUSION: Elevated CEA after neoadjuvant chemoradiation and clinical stage T4 disease were unfavourable predictors for overall and disease-free survival. Normalized CEA during neoadjuvant chemoradiation may serve as a prognosticator, although pretreatment CEA may significantly affect survival.

Total Neoadjuvant Treatment for Rectal Cancer: Preliminary Experience.

INTRODUCTION: Administration of chemotherapeutic regimens such as FOLFOX or CAPEOX with chemoradiation in the neoadjuvant setting, termed total neoadjuvant treatment (TNT), was introduced in recent years. By increasing the complete pathologic and clinical responses, patients with locally advanced rectal cancer may have better oncologic outcomes and potentially abstain from undergoing a proctectomy. METHODS: All patients who underwent TNT at a single National Accreditation Program for Rectal Cancer accredited referral center were included. A retrospective analysis was performed using a computerized Institutional Review Board-approved database. Patient demographics, diagnostic workup, treatment regimens, and surgical and pathological reports were reviewed. Complete pathological response was the primary outcome. Univariable and multivariable logistic regression analyses were performed to identify potential factors predisposing to complete pathological response. RESULTS: Thirty patients met the inclusion criteria, 14(46.6%) of whom had complete pathologic response. There was no difference in baseline demographic characteristics between patients who achieved complete pathological response and those who did not. Pathology revealed a 92% intact mesorectum rate in the complete pathologic response group and a mean of 24 harvested lymph nodes in the entire study cohort. Both univariable and multivariable logistic regression analyses failed to demonstrate statistically significant factors predicting complete pathologic response, magnetic resonance imaging (MRI) tumor size, and posttreatment MRI lymph node positivity. CONCLUSION: TNT is safe and efficient for patients with locally advanced rectal cancer. It increases complete pathological and clinical response rates and may more widely evolve to be the treatment of choice in this group of patients in the near future.

Practical and cost-effective model to build and sustain a cardio-oncology program.

BACKGROUND: Cardio-Oncology (CO) is a new subspecialty that thrives mostly in large academic quaternary centers. This study describes how to establish a successful cardio-oncology program, with limited resources, in order to effectively manage the unique care required by this patient population. METHODS: Clinical data was collected from 25 consecutive months. There were four foundational elements to establish a CO program: 1. Clinical program: integrating staff and resources from the Heart and Vascular, and Cancer Centers; 2. Education Program: establishing a platform to educate/advocate with respect to CO; 3. Engagement with professional societies: active engagement allowed for the successful establishment of the proposed CO program; and 4. Research program: establishing data collection modalities/cooperation with other institutions. RESULTS: 474 consecutive patients were treated by our CO program during the first 25 months of operation. Clinical data, information about cancer treatment, cardiovascular co morbidities, cardiac testing and impact of CO management are reported. CONCLUSIONS: A successful CO program can be established utilizing existing resources without the need for significant additional assets. Integration with professional societies, advocacy, education and research, provide a platform for learning and growth. This model improves access to care and can be reproduced in a variety of settings.

Ionic silver functionalized ovine forestomach matrix - a non-cytotoxic antimicrobial biomaterial for tissue regeneration applications.

BACKGROUND: Antimicrobial technologies, including silver-containing medical devices, are increasingly utilized in clinical regimens to mitigate risks of microbial colonization. Silver-functionalized resorbable biomaterials for use in wound management and tissue regeneration applications have a narrow therapeutic index where antimicrobial effectiveness may be outweighed by adverse cytotoxicity. We examined the effects of ionic silver functionalization of an extracellular matrix (ECM) biomaterial derived from ovine forestomach (OFM-Ag) in terms of material properties, antimicrobial effectiveness and cytotoxicity profile. METHODS: Material properties of OFM-Ag were assessed by via biochemical analysis, microscopy, atomic absorption spectroscopy (AAS) and differential scanning calorimetry. The silver release profile of OFM-Ag was profiled by AAS and antimicrobial effectiveness testing utilized to determine the minimum effective concentration of silver in OFM-Ag in addition to the antimicrobial spectrum and wear time. Biofilm prevention properties of OFM-Ag in comparison to silver containing collagen dressing materials was quantified via in vitro crystal violet assay using a polymicrobial model. Toxicity of ionic silver, OFM-Ag and silver containing collagen dressing materials was assessed toward mammalian fibroblasts using elution cytoxicity testing. RESULTS: OFM-Ag retained the native ECM compositional and structural characteristic of non-silver functionalized ECM material while imparting broad spectrum antimicrobial effectiveness toward 11 clinically relevant microbial species including fungi and drug resistant strains, maintaining effectiveness over a wear time duration of 7-days. OFM-Ag demonstrated significant prevention of polymicrobial biofilm formation compared to non-antimicrobial and silver-containing collagen dressing materials. Where silver-containing collagen dressing materials exhibited cytotoxic effects toward mammalian fibroblasts, OFM-Ag was determined to be non-cytotoxic, silver elution studies indicated sustained retention of silver in OFM-Ag as a possible mechanism for the attenuated cytotoxicity. CONCLUSIONS: This work demonstrates ECM biomaterials may be functionalized with silver to favourably shift the balance between detrimental cytotoxic potential and beneficial antimicrobial effects, while preserving the ECM structure and function of utility in tissue regeneration applications.

Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion.

PURPOSE: An ASCO provisional clinical opinion (PCO) offers timely clinical direction to ASCO's membership and other health care providers. This PCO addresses identification and management of patients and family members with possible predisposition to pancreatic adenocarcinoma. METHODS: ASCO convened an Expert Panel and conducted a systematic review of the literature published from January 1998 to June 2018. Results of the databases searched were supplemented with hand searching of the bibliographies of systematic reviews and selected seminal articles and contributions from Expert Panel members' curated files. PROVISIONAL CLINICAL OPINION: All patients diagnosed with pancreatic adenocarcinoma should undergo assessment of risk for hereditary syndromes known to be associated with an increased risk for pancreatic adenocarcinoma. Assessment of risk should include a comprehensive review of family history of cancer. Individuals with a family history of pancreatic cancer affecting two first-degree relatives meet criteria for familial pancreatic cancer (FPC). Individuals (cancer affected or unaffected) with a family history of pancreatic cancer meeting criteria for FPC, those with three or more diagnoses of pancreatic cancer in same side of the family, and individuals meeting criteria for other genetic syndromes associated with increased risk for pancreatic cancer have an increased risk for pancreatic cancer and are candidates for genetic testing. Germline genetic testing for cancer susceptibility may be discussed with individuals diagnosed with pancreatic cancer, even if family history is unremarkable. Benefits and limitations of pancreatic cancer screening should be discussed with individuals whose family history meets criteria for FPC and/or genetic susceptibility to pancreatic cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

E3611-A Randomized Phase II Study of Ipilimumab at 3 or 10 mg/kg Alone or in Combination with High-Dose Interferon-α2b in Advanced Melanoma.

PURPOSE: Interferon-α favors a Th1 shift in immunity, and combining with ipilimumab (ipi) at 3 or 10 mg/kg may downregulate CTLA4-mediated suppressive effects, leading to more durable antitumor immune responses. A study of tremelimumab and high-dose interferon-α (HDI) showed promising efficacy, supporting this hypothesis. PATIENTS AND METHODS: E3611 followed a 2-by-2 factorial design (A: ipi10+HDI; B: ipi10; C: ipi3+HDI; D: ipi3) to evaluate (i) no HDI versus HDI (across ipilimumab doses) and (ii) ipi3 versus ipi10 (across HDI status). We hypothesized that median progression-free survival (PFS) would improve from 3 to 6 months with HDI versus no HDI and with ipi10 versus ipi3. RESULTS: For eligible and treated patients (N = 81) at a median follow-up time of 29.8 months, median PFS was 4.4 months [95% confidence interval (CI), 2.7-8.2] when ipilimumab was used alone and 7.5 months (95% CI, 5.1-11.0) when HDI was added. Median PFS was 3.8 months (95% CI, 2.6-7.5) with 3 mg/kg ipilimumab and 6.5 months (95% CI, 5.1-13.5) with 10 mg/kg. By study arm, median PFS was 8.0 months (95% CI, 2.8-20.2) in arm A, 6.2 months (95% CI, 2.7-25.7) in B, 5.7 months (95% CI, 1.5-11.1) in C, and 2.8 months (95% CI, 2.6-5.7) in D. The differences in PFS and overall survival (OS) did not reach statistical significance. Adverse events were consistent with the known profiles of ipilimumab and HDI and significantly higher with HDI and ipi10. CONCLUSIONS: Although PFS was increased, the differences resulting from adding interferon-α or a higher dose of ipilimumab did not reach statistical significance and do not outweigh the added toxicity risks.

Mechanically Tunable Slippery Behavior on Soft Poly(dimethylsiloxane)-Based Anisotropic Wrinkles Infused with Lubricating Fluid.

We demonstrate a novel technique to fabricate mechanically tunable slippery surfaces using one-dimensional (anisotropic) elastic wrinkles. Such wrinkles show tunable topography (amplitude) on the application of mechanical strain. Following Nepenthes pitcher plants, lubricating fluid infused solid surfaces show excellent slippery behavior for test liquid drops. Therefore, combining the above two, that is, infusing suitable lubricating fluid on elastic wrinkles, would enable us to fabricate mechanically tunable slippery surfaces. Completely stretched (flat) wrinkles have uniform coating of lubricating fluid, whereas completely relaxed (full amplitude) wrinkles have most of the lubricating oil in the wrinkle grooves. Therefore, water drops on completely stretched surface show excellent slippery behavior, whereas on completely relaxed surface they show reduced slippery behavior. Therefore, continuous variation of wrinkle stretching provides reversibly tunable slippery behavior on such a system. Because the wrinkles are one-dimensional, they show anisotropic tunability of slippery behavior depending upon whether test liquid drops slip parallel or perpendicular to the wrinkles.